EP2252289A1 - Combination therapy comprising sglt inhibitors and dpp4 inhibitors - Google Patents

Combination therapy comprising sglt inhibitors and dpp4 inhibitors

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Publication number
EP2252289A1
EP2252289A1 EP09701670.3A EP09701670A EP2252289A1 EP 2252289 A1 EP2252289 A1 EP 2252289A1 EP 09701670 A EP09701670 A EP 09701670A EP 2252289 A1 EP2252289 A1 EP 2252289A1
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EP
European Patent Office
Prior art keywords
group
alkyl
ring
pharmaceutically acceptable
acceptable salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP09701670.3A
Other languages
German (de)
French (fr)
Other versions
EP2252289B1 (en
Inventor
Kiichiro Ueta
Kenji Arakawa
Yasuaki Matsushita
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mitsubishi Tanabe Pharma Corp
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Mitsubishi Tanabe Pharma Corp
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
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    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61K31/7008—Compounds having an amino group directly attached to a carbon atom of the saccharide radical, e.g. D-galactosamine, ranimustine
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    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
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    • C—CHEMISTRY; METALLURGY
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    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
    • C07H7/04—Carbocyclic radicals

Definitions

  • the present invention relates to compositions and methods for increasing plasma active GLP-I level in a mammal.
  • the present invention further relates to compositions and methods for ameliorating conditions by increasing plasma active GLP-I level.
  • Glucagon-like peptide-1 is an incretin hormone that is released from L-cells in lower small intestine after food intake. GLP-I has been shown to stimulate glucose-dependent insulin secretion from pancreatic ⁇ -cells and increase pancreatic ⁇ -cell mass. GLP-I has also been shown to reduce the rate of gastric emptying and promote satiety. However, GLP-I is rapidly cleaved by dipeptidyl peptidase 4 (DPP4) leading to inactivation of its biological activity. Therefore, DPP4 inhibitors are considered to be useful as anti-diabetics or anti-obesity agents.
  • DPP4 dipeptidyl peptidase 4
  • SGLTs Sodium-glucose co-transporters
  • Plasma glucose is filtered in the glomerulus and is reabsorbed by SGLTs in the proximal tubules. Therefore, inhibition of SGLTs cause excretion of blood glucose into urine and leads to reduction of plasma glucose level.
  • an SGLT inhibitor, phlorizin to diabetic animal models, the blood glucose level thereof can be normalized, and that by keeping the blood glucose level normal for a long time, the insulin secretion and insulin resistance can be improved [cf., Journal of Clinical Investigation, vol. 79, p. 1510 (1987); ibid., vol. 80, p. 1037 (1987); ibid., vol. 87, p. 561 (1991) ] .
  • SGLT inhibitors are expected to improve insulin secretion and insulin resistance by decreasing the blood glucose level in diabetic patients and to prevent the onset and progress of diabetes mellitus and diabetic complications.
  • the inventors of the present invention have found that administration of an SGLT inhibitor in combination with a DPP4 inhibitor can provide an unexpected synergistic effect in increasing plasma active GLP-I level in a patient over that provided by administration of the SGLT inhibitor or the DPP4 inhibitor alone.
  • the present invention relates to combination of an SGLT inhibitor and a DPP4 inhibitor such that the combination provides an effect in increasing plasma active GLP-I level in a patient over that provided by the SGLT inhibitor or the DPP4 inhibitor alone.
  • the present invention relates to use of combination of an SGLT inhibitor and DPP4 inhibitor for preventing or treating some sort of disease which is associated with plasma active GLP-I level.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an SGLT inhibitor and a DPP4 inhibitor for use in prevention or treatment of some sort of disease which is associated with plasma active GLP-
  • the present invention relates to a method of preventing or treating some sort of disease which is associated with plasma active GLP-I level comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising an SGLT inhibitor and a DPP4 inhibitor.
  • the present invention relates to use of an SGLT inhibitor and a DPP4 inhibitor for the manufacture of a medicament for the prevention or treatment of some sort of disease which is associated with plasma active GLP-I level.
  • the present invention relates to a product containing an SGLT inhibitor and a DPP4 inhibitor as a combined preparation for simultaneous, separate or sequential administration for preventing or treating a disease associated with plasma active GLP-I level.
  • diabetes encompasses both insulin-dependent diabetes mellitus (also known as Type 1 diabetes) and non-insulin-dependent diabetes mellitus (also known as Type 2 diabetes) .
  • diabetes which is associated with plasma active GLP-I level
  • diabetes includes diabetes, a condition related to diabetes, obesity, myocardial infarction, stroke, learning impairment, memory impairment, and a neurodegenerative disorder.
  • condition related to diabetes includes hyperglycemia, impaired glucose tolerance, impaired fasting glucose, insulin resistance, pancreatic beta-cell insufficiency, enteroendocrine cell insufficiency, glucosuria, metabolic acidosis, cataracts, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic coronary artery disease, diabetic cerebrovascular disease, diabetic peripheral vascular disease, metabolic syndrome, hyperlipidemia, atherosclerosis, stroke, hypertension, and obesity.
  • halogen refers to chlorine, bromine, fluorine and iodine, and chlorine and fluorine are preferable.
  • alkyl means a straight or branched saturated monovalent hydrocarbon chain having 1 to 12 carbon atoms, unless otherwise noted.
  • the straight chain or branched chain alkyl group having 1 to 6 carbon atoms is preferable, and the straight chain or branched chain alkyl group having 1 to 4 carbon atoms is more preferable.
  • alkyl examples include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2, 2 , 4-trimethylpentyl, nonyl, decyl, and various branched chain isomers thereof.
  • the alkyl group may optionally and independently be substituted by 1 to 4 substituents as listed below, if necessary.
  • alkylene means a straight or branched divalent saturated hydrocarbon chain having 1 to 12 carbon atoms, unless otherwise noted.
  • the straight chain or branched chain alkylene group having 1 to 6 carbon atoms is preferable, and the straight chain or branched chain alkylene group having 1 to 4 carbon atoms is more preferable.
  • Examples of alkylene include methylene, ethylene, propylene, and trimethylene . If necessary, the alkylene group. may optionally be substituted similarly to "alkyl" as mentioned above.
  • alkylene attaches at two different carbon atoms of the benzene ring, they form an annelated five, six or seven membered carbocycle together with the carbon atoms to which they are attached, and may optionally be substituted by one or more substituents defined below.
  • alkenyl means a straight or branched monovalent hydrocarbon chain having 2 to 12 carbon atoms and having at least one double bond, unless otherwise noted.
  • Preferable “alkenyl” is a straight chain or branched chain alkenyl group having 2 to 6 carbon atoms, and the straight chain or branched chain alkenyl group having 2 to 4 carbon atoms is more preferable.
  • alkenyl examples include vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3- pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, A- heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, A- dodecenyl, and 4, 8, 12-tetradecatrienyl .
  • the alkenyl group may optionally and independently be substituted by 1 to 4 substituents as mentioned below, if necessary.
  • alkenylene means a straight or branched divalent hydrocarbon chain having 2 to 12 carbon atoms and having at least one double bond, unless otherwise noted.
  • the straight chain or branched chain alkenylene group having 2 to 6 carbon atoms is preferable, and the straight chain or branched chain alkenylene group having 2 to 4 carbon atoms is more preferable.
  • Examples of alkenylene include vinylene, propenylene, butadienylene . If necessary, the alkenylene group may optionally be substituted by 1 to 4 substituents as mentioned below, if necessary.
  • an alkenylene group attaches at two different carbon atoms of a benzene ring, they form an annelated five, six or seven membered carbocycle (e.g., a fused benzene ring) together with the carbon atoms to which they are attached, and may optionally be substituted by one or more substituents defined below.
  • alkynyl means a straight or branched monovalent hydrocarbon chain having at least one triple bond, unless otherwise noted.
  • the preferable alkynyl group is a straight chain or branched chain alkynyl group having 2 to 6 carbon atoms, and the straight chain or branched chain alkynyl group having 2 to 4 carbon atoms is more preferable.
  • alkynyl examples include 2-propynyl, 3- butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3- hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3- nonynyl, 4-decynyl, 3-undecynyl, and 4-dodecynyl.
  • the alkynyl group may optionally and independently be substituted by 1 to 4 substituents as mentioned below, if necessary.
  • cycloalkyl means a monocyclic or bicyclic monovalent saturated hydrocarbon ring having 3 to 12 carbon atoms, unless otherwise noted, and the monocyclic saturated hydrocarbon group having 3 to 7 carbon atoms is more preferable.
  • Examples of cycloalkyl include monocyclic and bicyclic alkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl. These groups may optionally and independently be substituted by 1 to 4 substituents as mentioned below, if necessary.
  • the cycloalkyl group may optionally be condensed with a saturated hydrocarbon ring or an unsaturated hydrocarbon ring (said saturated hydrocarbon ring and unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO or SO 2 within the ring, if necessary) , and the condensed saturated hydrocarbon ring and the condensed unsaturated hydrocarbon ring may be optionally and independently be substituted by 1 to 4 substituents as mentioned below.
  • cycloalkylidene means a monocyclic or bicyclic divalent saturated hydrocarbon ring having 3 to 12 carbon atoms, unless otherwise noted, and the monocyclic saturated hydrocarbon group having 3 to 6 carbon atoms is preferable.
  • Examples of “cycloalkylidene” include monocyclic and bicyclic alkylidene such as cyclopropylidene, cyclobutylidene, cyclopentylidine, and eyelohexylidene . These groups may optionally and independently be substituted by 1 to 4 substituents as mentioned below, if necessary.
  • the cycloalkylidene group may optionally be condensed with a saturated hydrocarbon ring or an unsaturated hydrocarbon ring (said saturated hydrocarbon ring and unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO or SO 2 within the ring, if necessary) , and the condensed saturated hydrocarbon ring and the unsaturated hydrocarbon ring may be optionally and independently be substituted by 1 to 4 substituents as mentioned below.
  • cycloalkenyl means a monocyclic or bicyclic monovalent unsaturated hydrocarbon ring having 4 to 12 carbon atoms and having at least one double bond, unless otherwise noted.
  • the preferable cycloalkenyl group is a monocyclic unsaturated hydrocarbon group having 4 to 7 carbon atoms.
  • Examples of “cycloalkenyl” include monocyclic alkenyl such as cyclopentenyl, cyclopentadienyl, and cyclohexenyl . These groups may optionally and independently be substituted by 1 to 4 substituents as mentioned below, if necessary.
  • the cycloalkenyl group may optionally be condensed with a saturated hydrocarbon ring or an unsaturated hydrocarbon ring (said saturated hydrocarbon ring and unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO or SO 2 within the ring, if necessary) , and the condensed saturated hydrocarbon ring and the unsaturated hydrocarbon ring may be optionally and independently be substituted by 1 to 4 substituents as mentioned below.
  • cycloalkynyl means a monocyclic or bicyclic unsaturated hydrocarbon ring having 6 to 12 carbon atoms, and having at least one triple bond, unless otherwise noted.
  • the preferable cycloalkynyl group is a monocyclic unsaturated hydrocarbon group having 6 to 8 carbon atoms.
  • Examples of “cycloalkynyl” include monocyclic alkynyl such as cyclooctynyl, and cyclodecynyl . These groups may optionally be substituted by 1 to 4 substituents as mentioned below, if necessary.
  • the cycloalkynyl group may optionally and independently be condensed with a saturated hydrocarbon ring or an unsaturated hydrocarbon ring (said saturated hydrocarbon ring and unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO or SO 2 within the ring, if necessary)
  • the condensed saturated hydrocarbon ring or the unsaturated hydrocarbon ring may be optionally and independently be substituted by 1 to 4 substituents as mentioned below.
  • aryl or "Aryl” means a monocyclic or bicyclic monovalent aromatic hydrocarbon group having 6 to 10 carbon atoms, unless otherwise noted.
  • aryl include phenyl and naphthyl (including 1-naphthyl group and 2-naphthyl group) . These groups may optionally and independently be substituted by 1 to 4 substituents as mentioned below, if necessary.
  • the aryl group may optionally be condensed with a saturated hydrocarbon ring or an unsaturated hydrocarbon ring (said saturated hydrocarbon ring and unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO or SO 2 within the ring, if necessary) , and the condensed saturated hydrocarbon ring or the unsaturated hydrocarbon ring may be optionally and independently be substituted by 1 to 4 substituents as mentioned below.
  • saturated monocyclic heterocyclic ring means an unsaturated hydrocarbon ring containing 1-4 heteroatoms independently selected from a nitrogen atom, an oxygen atom and a sulfur atom, and the preferable one is a 4- to 7-membered saturated or unsaturated hydrocarbon ring containing 1-4 heteroatoms independently selected from a nitrogen atom, an oxygen atom and a sulfur atom, unless otherwise noted.
  • Examples of the unsaturated monocyclic heterocyclic ring are pyridine, pyrimidine, pyrazine, furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, 4, 5-dihydrooxazolyl, thiazole, isothiazole, thiadiazole, triazole, and tetrazole .
  • pyridine, pyrimidine, pyrazine, furan, thiophene, pyrrole, imidazole, oxazole, and thiazole can be preferably used.
  • the unsaturated monocyclic heterocyclic ring may optionally and independ- ently be substituted by 1-4 substituents as mentioned below, if necessary.
  • saturated fused heterobicyclic ring means a hydrocarbon ring comprised of a saturated or a unsaturated hydrocarbon ring condensed with the above mentioned unsaturated monocyclic heterocyclic ring where said saturated hydrocarbon ring and said unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO, or SO 2 within the ring, if necessary.
  • Examples of the unsaturated fused heterobicyclic ring include benzothiophene, indole, tetrahydrobenzothiophene, benzofuran, isoquinoline, thienothiophene, thienopyridine, quinoline, indoline, isoindoline, benzothiazole, benzoxazole, indazole, and dihydroisoquinoline .
  • the "heterocyclic ring” also includes possible N- or S-oxides thereof.
  • heterocyclyl means a monovalent group of the above-mentioned unsaturated monocyclic heterocyclic ring or unsaturated fused heterobicyclic ring and a monovalent group of the saturated version of the above- mentioned unsaturated monocyclic heterocyclic or unsaturated fused heterobicyclic ring. If necessary, the heterocyclyl may optionally and independently be substituted by 1 to 4 substituents as mentioned below.
  • alkanoyl includes formyl and alkyl linked to carbonyl, unless otherwise noted.
  • alkoxy includes alkyl linked to oxygen, unless otherwise noted.
  • substituent for the above each group includes halogen (e.g., fluorine, chlorine, bromine, and iodine) , nitro, cyano, oxo, hydroxy, mercapto, carboxyl, sulfo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyli- denemethyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkyloxy, cyclo- alkenyloxy, cycloalkynyloxy, aryloxy, heterocyclyloxy, alkanoyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkyl- carbonyl, cycloalkenylcarbonyl, cycloalkynylcarbonyl, arylcarbonyl, heterocyclylcarbonyl,
  • haloalkyl, halo-lower alkyl, haloalkoxy, halo-lower alkoxy, halophenyl, and haloheterocyclyl mean alkyl, lower alkyl, alkoxy, lower alkoxy, phenyl group or heterocyclyl (hereinafter, referred to as "alkyl, etc.") being substituted by one or more halogen, respectively.
  • alkyl, etc. being substituted by 1 to 7 halogen
  • more preferable examples include alkyl, etc., being substituted by 1 to 5 halogen.
  • hydroxy- alkyl, hydroxy-lower alkyl, hydroxyalkoxy, hydroxy-lower alkoxy and hydroxyphenyl mean alkyl, etc., being substituted by one or more hydroxy groups.
  • Preferable examples include alkyl, etc., being substituted by 1 to 4 hydroxy groups, and more preferable examples include alkyl., etc., being substituted by 1 to 2 hydroxy groups.
  • alkoxyalkyl lower alkoxyalkyl, alkoxy-lower alkyl, lower alkoxy-lower alkyl, alkoxyalkoxy, lower alkoxyalkoxy, alkoxy-lower alkoxy, lower alkoxy-lower alkoxy, alkoxyphenyl , and lower alkoxyphenyl means alkyl, etc., being substituted by one or more alkoxy groups.
  • Preferable examples include alkyl, etc., being substituted by 1 to 4 alkoxy groups, and more preferable examples include alkyl, etc., being substituted by 1 to 2 alkoxy groups .
  • arylakyl and arylalkoxy as used alone or as part of another group refer to alkyl and alkoxy groups as described above having an aryl substituent.
  • lower used in the definitions for the formulae in the present specification means a straight or branched carbon chain having 1 to 6 carbon atoms, unless defined otherwise. More preferably, it means a straight or branched carbon chain having 1 to 4 carbon atoms .
  • prodrug means an ester or carbonate, which can be formed by reacting one or more hydroxy groups of the compound used in the combination therapy of the present invention with an acylating agent by a conventional method.
  • ester include acetate, pivalate, methyl- carbonate, and benzoate.
  • prodrug also means an ester or amide, which can be similarly formed by reacting one or more hydroxy groups of the compound used in the combination therapy of the present invention with an ⁇ -amino acid or a ⁇ -amino acid using a condensing agent by a conventional method.
  • Examples of a pharmaceutically acceptable salt of SGLT inhibitors or DPP4 inhibitors include a salt with an alkali metal (e.g., lithium, sodium, and potassium); a salt with an alkaline earth metal (e.g., calcium, and magnesium) ; a salt with zinc or aluminum,- a salt with an organic base (e.g., ammonia, choline, diethanolamine, lysine, ethylenediamine , t-butylamine, t-octylamine, tris (hydroxymethyl) aminomethane , N-methyl-glucosamine, triethanolamine and dehydroabietylamine) ; a salt with an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid); a salt with an organic acid (e.g., formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succin
  • pharmaceutically acceptable salt used herein encompass solvates, and hydrates thereof.
  • stereochemically pure isomeric forms may be obtained by the methods well known to those skilled in the art. Diastereoisomers may be separated by physical separation methods such as fractional crystallization and chromatographic techniques, and enantiomers may be separated from each other by the selective crystallization of the diastereomeric salts with optically active acids or bases or by chiral chromatography. Pure stereoisomers may also be prepared synthetically from appropriate stereochemically pure starting materials, or by using stereospecific reactions.
  • SGLT inhibitors are well known to those skilled in the art, and examples of the SGLT inhibitors are described in many publications or patent literatures.
  • SGLT inhibitors are the C-aryl glucosides disclosed in WO 01/27128 pamphlet, which are represented by Formula (1) :
  • R 1 , R 2 and R 2a are independently hydrogen, OH, OR 5 , alkyl, CF 3 , OCHF 2 , OCF 3 , SR 5i or halogen, or two of R 1 , R 2 and R 2a together with the carbons to which they are attached can form an annelated five, six or seven membered carbocycle or heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, 0, S, SO, and/or SO 2 ; R 3 and R 4 are independently hydrogen, OH, 0R 5a , OAryl,
  • R 5 , R 5a , R 5b , R 5C , R 5d , R 5e , R 5f , R 5g , R 5h and R 5i are independently alkyl;
  • R 5 , R Sa , R ⁇ b , R ec and R sd are independently hydrogen, alkyl, aryl, alkylaryl or cycloalkyl, or R 6 and R 5a together with the nitrogen to which they are attached form an annelated five, six or seven membered heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, 0, S, SO, and/or SO 2 ;
  • A is 0, S, NH, or (CH 2 ) n where n is 0-3, and a pharmaceu- tically acceptable salt thereof, all stereoisomers thereof, and all prodrug esters thereof.
  • the SGLT inhibitor is Dapagliflozin represented by Formula (2) :
  • the SGLT inhibitor is the C-aryl glucoside compound disclosed in WO 2006/034489 pamphlet, which is represented by Formula (3) :
  • the SGLT inhibitors are 0-aryl glucoside compounds disclosed in WO 01/74834 pamphlet, which are represented by Formula (4) :
  • R 1 , R 2 , R 3 , and R 4 are the same or different and are independently selected from hydrogen, OH, OR 7 , lower alkyl, or halogen, or two of R 1 , R 2 , R 3 , and R 4 together with the carbons to which they are attached can form an annelated five, six or seven membered carbocycle or heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO 2 ;
  • R 5 and R 6 are the same or different and are independently selected from hydrogen, OH, 0R 7a , -OAryl, -0CH 2 Aryl, lower alkyl, cycloalkyl, Aryl, arylalkyl, CF 3 , arylalkenyl, -OCHF 2 , -OCF 3 , halogen, -CN, -CO 2 R 7b , -CO 2 H, COR 8f , CHOHR 8g , CH(OR 7h )R 8h , -CONR 8 R 8a , -NHCOR 70 , -NHS0 2 R 7d , -NHS0 2 Aryl, -SR 7e , -SOR 7f , -SO 2 R 7g , -S0 2 Aryl, -OCH 2 CO 2 R 71 , -OCH 2 CO 2 H, -OCH 2 CONR 8b R 8c , -OCH 2 CH 2 NR 8d R
  • the SGLT inhibitors are the glucopyranosyloxybenzylbenzene derivatives disclosed in WO 02/028872 pamphlet, which are represented by Formula (5) :
  • P represents a group forming a prodrug
  • R represents lower alkyl, lower alkoxy, lower alkylthio, lower alkoxy-substituted lower alkyl, lower alkoxy- substituted lower alkoxy or lower alkoxy-substituted lower alkylthio.
  • the SGLT inhibitors are the glucopyranosyloxybenzyl-benzene derivatives disclosed in WO 01/68660 pamphlet, which are represented by Formula (6) :
  • R 1 represents hydrogen or hydroxy (lower alkyl) ; and R 2 represents lower alkyl, lower alkoxy, lower alkylthio, hydroxy (lower alkyl), hydroxy (lower alkoxy), hydroxy (lower alkylthio) , lower alkoxy-substituted (lower alkyl) , lower alkoxy-substituted (lower alkoxy) or lower alkoxy-substituted (lower alkylthio) , or a pharmaceutically acceptable salt thereof .
  • the SGLT inhibitor is Sergliflozin represented by Formula (7) :
  • the SGLT inhibitor is Sergliflozin-A represented by Formula (8) :
  • the SGLT inhibitors are the glucopyranosyloxypyrazole derivatives disclosed in WO 02/053573 pamphlet, which are represented by Formula (9) :
  • R represents hydrogen, lower alkyl or a group forming a prodrug,- one of Q and T represents a group represented by the formula:
  • R 2 represents hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halo (lower alkyl) or halogen; with the proviso that P does not represent hydrogen when R represents hydrogen or lower alkyl, or a pharmaceutically acceptable salt thereof .
  • the SGLT inhibitor is Remogliflozin represented by Formula (9a) :
  • the SGLT inhibitors are the compounds disclosed in WO 2005/085265 pamphlet, which are represented by Formula (10) :
  • R 1 and R 4 represents a group of the formula:
  • R 5 and R 6 independently represent hydrogen, hydroxy, halogen, C ⁇ - 6 alkyl , C 2 - 6 alkenyl, C 2 - 6 alkynyl, Ci_ s alkoxy, C 2 _ s alkenyloxy, C 1-6 alkylthio, C 2 - ⁇ alkenylthio, halo (Ci-s alkyl), halo(Ci- e alkoxy), halo (C 1 -S alkylthio), hydroxy (C 1 -S alkyl) , hydroxy (C 2 - 6 alkenyl) , hydroxy (C 1 -S alkoxy) , hydroxy (C 1 -S alkylthio) , carboxy, carboxy (C 1 -S alkyl) , carboxy (C 2 - S alkenyl) , carboxy (C ⁇ - S alkoxy) , carboxy(Ci- e alkylthio), C 2 _ 7 alk
  • J represents C 1 - S alkylene which may have hydroxy, or C 2 - ⁇ alkenylene;
  • U represents -O- , -S- or a single bond and with the proviso that at least one of V and W is not a single bond when U is -0- or -S-;
  • V represents C 1 -S alkylene which may have hydroxy, C 2 - ⁇ alkenylene or a single bond
  • R E , R F and R G independently represent hydrogen, cyano, carbamoyl, C 2 -7 acyl, C 2 -7 alkoxycarbonyl, Cg-io aryl (C 2 - ⁇ alkoxycarbonyl) , nitro, C 1 -S alkylsulfonyl, sulfamide, carbamimidoyl or C 1 - S alkyl which may have 1 to 5 substituents selected from the following substituent group ⁇ ; or R E and R F bind together to form ethylene; or R F and R G bind together with the neighboring nitrogen to form aliphatic cyclic amino which may have any substituent selected from the following substituent group ⁇ ,- Q represents -C 1 -S alkylene-, -C 2 -
  • R 2 and R 3 independently represent hydrogen, hydroxy, amino, halogen, Ci- e alkyl, Ci- 6 alkoxy, cyano, carboxy, C 2 - 7 alkoxycarbonyl, carbamoyl, mono or di (Ci_ 6 alkyl) amino, halo (Ci-s alkyl), hydroxy (Ci_ s alkyl), cyano (Ci_ s alkyl), carboxy (Ci- ⁇ alkyl), C 2 -7 alkoxycarbonyl (Ci- S alkyl), carbamoyl (Ci-s alkyl), amino (Ci_ 6 alkyl), mono or di (Ci- e alkyl) amino (Ci- 6 alkyl), halo(Ci- 6 alkoxy), hydroxy(Ci- 6 alkoxy), carboxy (Ci_ 6 alkoxy), C 2 - 7 alkoxycarbonyl (Ci_ 6 alkoxy), carbamoyl (C x - e al
  • a 1 represents 0, S or NR 9 ;
  • a 2 represents CH or N,- R 9 represents hydrogen or Ci_ 6 alkyl;
  • G represents a group represented by a formula:
  • E 1 represents hydrogen, fluorine or hydroxy
  • E 2 represents hydrogen, fluorine, methyl or hydroxymethyl
  • alkoxy- carbonyl C 1 -S alkyl
  • R H and R 1 independently represent hydrogen or C 1 -S alkyl which may have 1 to 3 substituents selected from the following substituent group ⁇ ,- or both of R H and R 1 bind together with the neighboring nitrogen to form aliphatic cyclic amino which may have 1 to 3 substituents selected from the following substituent group ⁇ ; [substituent group ⁇ ] halogen, hydroxy, amino, Ci_ 6 alkoxy, halo(Ci- 5 alkoxy), hydroxy (Ci- 6 alkoxy) , amino (Ci- 6 alkoxy) , mono or di (C 1 -S alkyl) amino, mono or di [hydroxy (C x _ 6 alkyl) ] amino, ureido,
  • alkoxycarbonyl, sulfamoyl and -CON (R J ) R ⁇ R J and R ⁇ independently represent hydrogen or C 1 -S alkyl which may have any 1 to 3 substituents selected from hydroxy, amino, mono or di (C 1 -S alkyl) amino, C 2 - 7 alkoxy- carbonyl and carbamoyl; or both of R J and R ⁇ bind together with the neighboring nitrogen to form aliphatic cyclic amino which may have any 1 to 3 substituents selected from hydroxy, amino, mono or di (C 1 -S alkyl) amino, C 1 -S alkyl, hydroxy (C 1 -S alkyl), C 2 -7 alkoxycarbonyl, C 2 - 7 alkoxycarbonyl (C 1 - S alkyl) and carbamoyl, or a pharmaceutically acceptable salt thereof, or a prodrug thereof .
  • the SGLT inhibitors are the compounds disclosed in WO 2005/085267 pamphlet, which are represented by Formula (11) : wherein
  • R 1 represents hydrogen, Ci- e alkyl, halo(Ci_ 6 alkyl) , hydroxy (Ci- 6 alkyl) , dihydroxy (C 1 - S alkyl) , Ci- S alkoxy (C 1-6 alkyl), C 2 -7 alkoxycarbonyl (C 1-5 alkyl), carboxy(C 1-s alkyl), C 2 -S alkenyl, -J-N(R 5 ) -Z 1 , -J-CON (R 5 ) -Z 1 , or any of the following substituents (a) to (d) which may have any 1 to 3 substituents selected from the following substituent group ⁇ on the ring,- (a) C 3-7 cycloalkyl, (b) C 3 - 7 cycloalkyl (C 1-6 alkyl), (c) C 6 _ 10 aryl or (d) C 1 -S aryl (C ⁇ _ 10 alkyl), R 2 represents hydrogen, hal
  • J represents C 1 - 6 alkylene which may have hydroxy, or C 2 -s alkenylene;
  • U represents -0- , -S- or a single bond and with the proviso that at least one of V and W is not a single bond when U is -0-or -S-) ;
  • V represents Ci- 6 alkylene which may have hydroxy, C 2 -s alkenylene or a single bond;
  • R 5 , R 5 , R A , R c and R D independently represent hydrogen, C 1 - S alkyl which may have any 1 to 5 substituents selected from the following substituent group ⁇ or any of the following substituents (xxix) to (xxxii) which may have any 1 to 3 substituents selected from the following substituent group Ct;
  • R B represents C 2 _ 7 alkoxycarbonyl , Ci_ ⁇ alkylsulfonylamino, C 6 -Io arylsulfonylamino, C 1 . 6 alkyl which may have any 1 to 5 substituents selected from the following substituent group ⁇ or any of the following substituents (xxxiii) to (xxxvi) which may have any 1 to 3 substituents selected from the following substituent group ⁇ ,-
  • R E , R F and R G independently represent hydrogen, cyano, carbamoyl, C 2 - 7 acyl group, C 2 _ 7 alkoxycarbonyl, C s _i 0 aryl (C 2 - 7 alkoxycarbonyl), nitro, C ⁇ - 6 alkylsulfonyl, sulfamoyl, carbamimidoyl or Ci_ e alkyl which may have any 1 to 5 substituents selected from the following substituent group ⁇ ; or R E and R F bind together to form ethylene; or R F and R G bind together with the neighboring nitrogen to form aliphatic cyclic amino which may have a substituent selected from the following substituent group ⁇ ,- Y represents CH or N;
  • Q represents -C 1 . 6 alkylene-, -C 2 -e alkenylene-, -C 2 - e alkynylene-, -Ci_ 6 alkylene-O-, -Ci- 6 alkylene-S-, -O-C ⁇ _ 6 alkylene-, -S-Cx-g alkylene-, -C 1 -S alkylene-0-C ⁇ -e alkylene-, -C 1 - S alkylene-S-Ci-e alkylene-, -CON(R 7 )-, -N (R 7 ) CO-, -C 1 -S alkylene-CON(R 7 ) - or -CON (R 7 ) -C 1 - S alkylene-;
  • R 7 represents hydrogen or Ci- S alkyl;
  • ring A represents C 6 - 10 aryl or heteroaryl;
  • G represents a group represented by a formula:
  • E 1 represents hydrogen, fluorine or hydroxy
  • E 2 represents hydrogen, fluorine, methyl or hydroxymethyl
  • [substituent group ⁇ ] halogen, hydroxy, amino, Ci_ 6 alkyl, Ci_ s alkoxy, halo(Ci_ s alkyl), halo (Ci- e alkoxy), hydroxy (Ci_ s alkyl), C 2 -7 alkoxy- carbonyl (Ci- 6 alkyl), hydroxy (C x - S alkoxy), amino (Ci- 6 alkyl), amino (Ci- 6 alkoxy), mono or di(Ci.
  • R J and R ⁇ independently represent hydrogen or Ci- S alkyl which may have any 1 to 3 substituents selected from hydroxy, amino, mono or di(Ci- s alkyl) amino, C 2 - 7 alkoxycarbonyl and carbamoyl ; or both of R ⁇ and R ⁇ bind together with the neighboring nitrogen to form aliphatic cyclic amino which may have any 1 to 3 substituents selected from hydroxy, amino, mono or di(Ci_s alkyl) amino, C 1 -S alkyl, hydroxy (Ci- S alkyl), C 2 .
  • the SGLT inhibitors are the glucopyranosyloxypyrazole derivatives disclosed in WO 01/16147 pamphlet, which are represented by Formula (12) :
  • R 1 represents hydrogen or lower alkyl ; one of Q 1 and T 1 represents a group represented by the formula:
  • R 2 represents hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halo (lower alkyl) or halogen, or a pharmaceutically acceptable salt thereof.
  • the SGLT inhibitors are the compounds disclosed in WO 2006/035796 pamphlet, which are represented by Formula (13) :
  • Ring A represents aryl or heteroaryl, each of which may have a substituent (s)
  • Q 1 to Q 5 are each independently carbon to which hydrogen or a substituent is connected, or nitrogen
  • E represents a single bond, alkylene, -0-, -S- or -NH-
  • R represents methyl, ethyl, fluoromethyl or hydroxymethyl , or a prodrug thereof or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
  • the SGLT inhibitors are the azulene derivatives disclosed in WO 2004/013118 pamphlet, which are represented by Formula (14) :
  • the SGLT inhibitors are the compounds disclosed in WO 2004/080990 pamphlet, which are represented by Formula (15) :
  • a ring represents (1) benzene, (2) five or six- membered monocyclic heteroaryl having 1 to 4 hetero atom(s) selected from N, S, and 0, or (3) saturated or unsaturated eight to ten-membered heterobicyclic having 1 to 4 hetero atom(s) selected from N, S, and 0;
  • B ring represents (1) saturated or unsaturated eight to ten-membered heterobicyclic having 1 to 4 hetero atom(s) selected from N, S, and 0, (2) saturated or unsaturated five or six-membered heteromonocyclic having 1 to 4 hetero atom(s) selected from N, S, and O, (3) a saturated or an unsaturated eight to ten-membered bicyclic hydrocarbon, or (4) benzene;
  • the SGLT inhibitors are represented by Formula (15a) :
  • R ⁇ represents a hydrogen atom, halogen atom, -OH, -OMe, -CH 2 -OH, -O- (CH 2 ) 2 -OH, -O- (CH 2 ) 2-NH 2 , -COOH, -COOEt, -0-CH 2 -COOH, or -0-CH 2 -COOEt
  • R 7 represents a hydrogen atom or halogen atom
  • R 8 represents a hydrogen atom, or -Me
  • R 9 represents a hydrogen atom, -Me, halogen atom, or -OMe.
  • the SGLT inhibitors are the glucopyranosyl-substituted benzene derivatives disclosed in WO 2005/092877 pamphlet, which are represented by Formula (16) :
  • R 1 is selected from the definitions of the group A, and if R 3 is selected from the definitions of the group B, R 1 may additionally be selected from hydrogen, fluorine, chlorine, bromine, iodine, C 3 .-4 alkyl, C 2 _ 4 aikenyl-Ci_ 4 alkyl, C 2 -4 alkynyl-Ci-4 alkyl, C 2 .
  • R 2 denotes hydrogen, fluorine, chlorine, bromine, hydroxy, Ci- 4 alkyl, Ci- 4 alkoxy, cyano or nitro, while the alkyl or alkoxy group may be mono- or polysubstituted by fluorine;
  • R 3 is selected from the definitions of the group B, and if R 1 is selected from the definitions of the group A, R 3 may additionally be selected from the meanings hydrogen, fluorine, chlorine, bromine, iodine, C x - 6 alkyl, C 2 . 4 alkenyl-Ci- 4 alkyl, C 2 - 4 alkynyl-Ci- 4 alkyl, C 2 .
  • R 4 and R 5 independently of one another denote hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, C x - 3 alkyl, C x-3 alkoxy, or methyl or methoxy substituted by 1 to 3 fluorine,
  • A denotes C 2-6 alkyn-1-yl, C 2 - 6 alken-1-yl, C 3 .
  • B denotes tri- (Ci- 4 alkyl) silyl-Ci_ ⁇ alkyl, C 2 - ⁇ alkyn-1-yl, C 2 -e alken-1-yl, amino, Ci_ 3 alkylamino, di- (Ci- 3 alkyl) amino, pyrrolidin-1-yl, pyrrolidin-2-on-l-yl, piperidin-1-yl, piperidin-2-on-l-yl, morpholin-4-yl, morpholin-3-on-4-yl, piperazin-1-yl, 4- (Ci- 3 alkyl)piperazin-l-yl, arylcarbonylamino, heteroarylcarbonylamino, nitro, C 3 - I0 cycl
  • R N denotes H, Ci_ 4 alkyl, Ci- 4 alkylcarbonyl or Ci- 4 alkyl- sulfonyl,
  • L 1 independently of one another is selected from hydroxy, cyano, nitro, C 3-7 cycloalkyl, aryl, heteroaryl, C 1 ⁇ 4 alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aminocarbonyl , Ci-4 alkylaminocarbonyl, di- (Ci_ 3 alkyl) -aminocarbonyl , pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin- 4-ylcarbonyl, arylaminocarbonyl , heteroarylaminocarbonyl , Ci-4 alkoxycarbonyl, aryl-C 1 .
  • L 2 independently of one another is selected from fluorine, chlorine, bromine, iodine, C x-3 alkyl, difluoromethyl, trifluoromethyl, Ci- 3 alkoxy, difluoromethoxy, trifluoro- methoxy and cyano;
  • R s , R 7a , R 7b , and R 7c independently of one another have a meaning selected from hydrogen, (C 1 - I8 -alkyl) carbonyl, (C 1 - i8-alkyl) oxycarbonyl, arylcarbonyl and aryl- (C 1 ⁇ 3 alkyl) - carbonyl, while the aryl group mentioned in the definition of the above groups are meant phenyl or naphthyl group which may be mono- or di-substituted independently of one another by identical or different groups L 2 ; and the heteroaryl group mentioned in the definition of the above groups are meant a pyrrolyl, furanyl, thienyl, pyridyl, indolyl, benzofuranyl , benzothiophenyl, quinolinyl, isoquinolinyl or tetrazolyl group, or is meant pyrrolyl, furanyl, thienyl or pyri
  • the SGLT inhibitor is the compound disclosed in WO 2006/117359 pamphlet, which is represented by Formula (17) :
  • the SGLT inhibitor is the compound disclosed in WO 2006/117360 pamphlet, which is represented by Formula (18) :
  • the SGLT inhibitors are the propiophenone derivatives disclosed in U.S. Pat. No. 6,048,842, or a pharmaceutically acceptable salt thereof, which are represented by Formula (19) : wherein OX is a hydroxy group which may optionally be protected, Y is a lower alkyl group, and Z is a ⁇ -D-gluco- pyranosyl group wherein one or more hydroxy groups may optionally be protected.
  • the SGLT inhibitors are the propiophenone derivatives disclosed in U.S. Pat. No. 5,830,873, or a pharmaceutically acceptable salt thereof, which are represented by Formula (20) :
  • X is an oxygen atom, a sulfur atom or a methylene group
  • OY is a protected or unprotected hydroxy group
  • Z is a ⁇ -D-glucopyranosyl group or 4-0- ( ⁇ -D-glucopyranosyl) - ⁇ -D- glucopyranosyl group wherein one or more hydroxy groups of these groups may optionally be acylated, and the dotted line means the presence or absence of a double bond.
  • the SGLT inhibitors are the propiophenone derivatives or a pharmaceutically acceptable salt thereof, disclosed in U.S. Pat No. 5,767,094, which are represented by Formula (21) : wherein R 1 is a lower alkanoyl group, and R" is a hydrogen atom, or R 1 is a hydrogen atom, and R" is a lower alkoxy- carbonyl group .
  • the SGLT inhibitor is the propiophenone derivatives or a pharmaceutically acceptable salt thereof disclosed in U.S. Pat. Nos . 5,424,406 and 5,731,292, which are represented by Formula (22) :
  • Ar is an aryl group
  • R 1 is hydrogen atom or an acyl group
  • R 2 is hydrogen atom, an acyl group or ⁇ -D-gluco- pyranosyl group, or R 1 and R 2 may combine together to form a substituted methylene group
  • R 3 and R 4 are each hydrogen atom or an acyl group
  • OR 5 is a protected or unprotected hydroxy group or a lower alkoxy group .
  • the SGLT inhibitors are the compounds disclosed in United States
  • Ring A and Ring B are one of the followings: (1) Ring A is optionally substituted unsaturated heteromono- cyclic, and Ring B is optionally substituted unsaturated heteromonocyclic, optionally substituted unsaturated fused heterobicyclic, or optionally substituted benzene, (2) Ring A is optionally substituted benzene, and Ring B is optionally substituted unsaturated heteromonocyclic, or optionally substituted unsaturated fused heterobicyclic wherein Y is linked to the heterocyclic ring of said fused heterobicyclic, or (3) Ring A is optionally substituted unsaturated fused heterobicyclic, wherein the sugar moiety X- (sugar) and the moiety -Y- (Ring B) are both on the same heterocyclic ring of said fused heterobicyclic, and Ring B is optionally substituted unsaturated heteromonocyclic, optionally substituted unsaturated unsaturated
  • X is carbon or nitrogen
  • Y is - (CH 2 ) n- (wherein n is 1 or 2) ; a pharmaceutically acceptable salt thereof, or a prodrug thereof .
  • the SGLT inhibitors are the compounds of Formula (24) :
  • R A is a halogen atom, or a lower alkyl group
  • Ring C is a phenyl group substituted by 1-3 substituents selected from the group consisting of a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group, a methylenedioxy group, an ethyleneoxy group, a mono- or di- lower alkylamino group, a carbamoyl group, and a mono- or di-lower alkylcarbamoyl group,- or a heterocyclyl group substituted by 1-3 substituents selected from the group consisting of a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group, a mono- or
  • Examples of the preferable compounds include:
  • the SGLT inhibitors are the indole derivatives disclosed in WO 2006/080577 pamphlet, which are represented by Formula (25) :
  • R 1 is halogen, or alkyl
  • R 2 is hydrogen, or halogen
  • Ar is one of the following groups
  • R 3 and R 4 are independently hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, hydroxy, phenyl, halophenyl, cyanophenyl, pyridyl, halo- pyridyl, thienyl, or halothienyl, or R 3 and R 4 together with carbon atoms to which they are attached form a fused benzene, furan or dihydrofuran ring,- or a pharmaceutically acceptable salt thereof.
  • Examples of the preferable compounds include: 4-chloro-3- (4-ethylphenylmethyl) -1- ( ⁇ -D-glucopyranosyl) - indole ;
  • the SGLT inhibitors are the indole derivatives disclosed in PCT/JP2007/065213, which are represented by Formula (26) :
  • R 1 is fluorine, or chlorine
  • R 2 is hydrogen, or fluorine, or a pharmaceutically acceptable salt thereof.
  • the preferable compounds include :
  • the SGLT inhibitors are the compounds disclosed in United States Patent Application Publication No. 2004/0259819, which are represented by Formula (27) : wherein
  • Rl and R2 are each independently F or H or one of said radicals Rl and R2 may be OH;
  • R3 is OH or F, with the proviso that at least one of the radicals Rl, R2 and R3 must be F;
  • R4 is OH
  • A is 0, NH, CH 2 , S or a bond
  • X is C, 0, S or N, with the proviso that X is C when Y is 0 or S;
  • R5 is hydrogen, F, Cl, Br, I, OH, CF 3 , NO 2 , CN, COOH, CO(C 1 - s alkyl) , COO(C 1 - S alkyl) , CONH 2 , CONH(C 1 _ 6 alkyl) , CON(C 1 -S alkyl) 2 , C ⁇ 6 alkyl, C 2 - S alkenyl, C 2 - 6 alkynyl, C 1 -S alkoxy,
  • Ci- ⁇ alkoxycarbonyl wherein said CO(C 1 -S alkyl), COO(C 1 -S alkyl), CONH(C 1 -S alkyl), CON(C 1 -S alkyl) 2 , C 1 -S alkyl, C 2 - 6 alkenyl, C 2 - e alkynyl, C 1 -S alkoxy, HO-(C 1 -S alkyl), (C 1 -S alkyl) -0- (C 1 -S alkyl) and C 1 - S alkoxycarbonyl radicals are optionally substituted with one or more fluorine atoms,
  • Cycl is a 3-, 4-, 5-, 6- or 7-membered saturated, partially saturated or unsaturated ring, wherein one carbon atom of said ring may be replaced by 0, N or S;
  • R7, R8 , and R9 are each independently hydrogen, F, Cl, Br, I, OH, CF 3 , NO 2 , CN, COOH, COO(C 1 -S alkyl), CO(Ci_ 4 alkyl), CONH 2 , CONH(C 1 -S alkyl), CON(C 1 -S alkyl) 2 , C 1 -S alkyl, C 2 - 6 alkenyl, C 2 .
  • the SGLT inhibitors are the compounds in United States Patent Application Publication No. 2005/0014704, which are represented by Formula (28) :
  • Rl, R2 are each independently OH, F or H with the proviso that when Rl is F, R2 cannot be OH; when Rl is OH, R2 cannot be F; and when Rl is OH, R2 cannot be OH; R3 is OH or F, with the proviso that at least one of said Rl, R2 , R3 radicals must be F,- A is 0, NH, CH 2 , S or a bond;
  • R4, R5, and R6 are each independently hydrogen, F, Cl, Br, I, OH, NO 2 , CN, COOH, CO(C 1 -S alkyl) , COO(CL 6 alkyl) , CONH 2 , CONH(Ci-S alkyl), CON(C 1 -S alkyl) 2 , Q ⁇ 6 alkyl, C 2 - s alkenyl, C 2 - S alkynyl, C x-6 alkoxy, HO (Ci.
  • R7, R8, R9 R7, R8 , and R9 are each independently hydrogen
  • s alkynyl, C 1 - S alkoxy, HO-(C x -S alkyl) and (C 1 -S alkyl) -0- (Ci- 6 alkyl) radicals are optionally substituted with one or more fluorine atoms,
  • Ci- S alkyl, C 2 - s alkenyl or C 2 -s alkynyl wherein said Ci_ s alkyl, C 2 . 5 alkenyl and C 2 -s alkynyl radicals are optionally substituted with F, Cl, OH, CF 3 , NO 2 , CN, COO(CL 4 alkyl), CONH 2 , CONH (Ci- 4 alkyl) or OCF 3 , and wherein a -CH 2 - group contained in said Ci_ 6 alkyl, C 2 - 5 alkenyl and C 2 - 5 alkynyl radicals is optionally replaced by -0-; and pharmaceutically acceptable salts thereof.
  • DPP4 inhibitors are well known to those skilled in the art, and examples of DPP4 inhibitors can be found in the following publications: (1) TANABE SEIYAKU Co., Ltd.: WO 02/30891 or the corresponding U.S. patent (No. 6,849,622); and WO 02/30890 or the corresponding U.S. patent (No. 7,138,397); .
  • GlaxoSmithKline WO 03/002531, WO 03/002530, and WO 03/002553;
  • Bristol Myers Squibb WO 01/68603, WO 02/83128, and WO 2005/012249;
  • DPP4 inhibitors are the aliphatic nitrogen-containing 5- membered ring compounds disclosed in US 6,849,622, which are represented by Formula (29) :
  • A represents -CH 2 - or -S-
  • R 1 represents hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group or a lower alkoxy lower alkyl group
  • R 2 represents (1) a cyclic group which may be substituted, where the cyclic group portion is (i) a monocyclic, bicyclic or tricyclic hydrocarbon group, or (ii) a monocyclic, bicyclic or tricyclic heterocyclic group, or (2) an amino group which may be substituted, or a pharmaceutically acceptable salt thereof .
  • Examples of the preferable compounds include:
  • DPP4 inhibitors are the aliphatic nitrogen-containing 5-membered ring compounds disclosed in US 7,138,397, which are represented by Formula (30) :
  • A is -CH 2 -
  • R 1 is H, a lower alkyl group, a hydroxy lower alkyl group or a lower alkoxy lower alkyl group
  • R 2 is a piperazinyl group which may be substituted, or a pharmaceutically acceptable salt thereof.
  • Examples of the preferable compounds include:
  • DPP4 inhibitors are the compounds disclosed in US 7,074,794, which are represented by Formula (31) :
  • X is -NR 1 R 2 wherein R 1 and R 2 may be the same or different and each is independently cycloalkylalkyl, arylalkyl, heteroaryl or heteroarylalkyl , or may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents, and the heterocycle optionally being a spiro ring, -NR 3 COR 4 wherein R 3 and R 4 are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl or heteroarylalkyl,
  • R 5 , R s and R 7 are the same or different and each is independently hydrogen atom, alkyl, acyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or R e and R 7 may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents,
  • a more preferable compound is 3- [ (2S, 4S) -4- [4- (3 -methyl-1-phenyl-lH-pyrazol-5 -yl)piperazin- 1-yl] pyrrolidin-2-yl] thiazolidine or a pharmaceutically acceptable salt thereof (e.g., hydrobromide) .
  • the DPP4 inhibitor is Sitagliptin [developing code: MK- 0431; proprietary name: Januvia; chemical name: (3R) -3 -amino-1- [9- (trifluoromethyl) -1,4,7, 8-tetraza- bicyclo [4.3.0] nona-6 , 8-dien-4-yl] -4- (2,4, 5-trifluoro- phenyl) butan-1-one] , or an equivalent thereof such as a pharmaceutically acceptable salt thereof (e.g., phosphate).
  • Sitagliptin developing code: MK- 0431; proprietary name: Januvia; chemical name: (3R) -3 -amino-1- [9- (trifluoromethyl) -1,4,7, 8-tetraza- bicyclo [4.3.0] nona-6 , 8-dien-4-yl] -4- (2,4, 5-trifluoro- phenyl) butan-1-one] , or an equivalent thereof such as a pharmaceutical
  • the DPP4 inhibitor is Vildagliptin [developing code: LAF237; proprietary name: Galvus ; chemical name: (2S) -1- [2- [ (3 -hydroxy-1-adamantyl) amino] acetyl] pyrrolidine- 2-carbonitrile] , or an equivalent thereof such as a pharmaceutically acceptable salt thereof .
  • the DPP4 inhibitor is Saxagliptin (developing code: BMS-477118; chemical name : (IS 7 3S, 5S) -2- [ (2S) -2- amino-2- (3 -hydroxy-1-adamantyl) acetyl] -2-azabicyclo [3.1.0]- hexane-3-carbonitrile) , or an equivalent thereof such as a pharmaceutically acceptable salt thereof.
  • the DPP4 inhibitor is Alogliptin (developing code: SYR-322; chemical name: 6- [ (3R) -3-aminopiperidin-l- yl] -1- (2-cyanobenzyl) -3-methylpyrimidin-2, 4 (IH, 3H) -dione) , or an equivalent thereof such as a pharmaceutically acceptable salt thereof (e.g., benzoate) .
  • the DPP4 inhibitor is L-threo-isoleucyl pyrrolidide, L-allo-iso- leucyl thiazolidide, or L-allo-isoleucyl pyrrolidide, or a pharmaceutically acceptable salt thereof.
  • the present invention relates to a method for treating or preventing a disease which is associated with plasma active GLP-I level comprising administering to a patient in need thereof a therapeutically effective amount of an SGLT inhibitor and a DPP4 inhibitor in combination.
  • the SGLT inhibitor and the DPP4 inhibitor are administered in amounts sufficient to lower a blood glucose level in the patient.
  • the present invention relates to a method for increasing plasma active GLP-I level comprising administering to a patient a therapeutically effective amount of an SGLT inhibitor and a DPP4 inhibitor in combination.
  • the SGLT inhibitor and the DPP4 inhibitor are administered in amounts sufficient to increase plasma active GLP-I level in the patient .
  • a combination therapy of the present invention is useful in treating or preventing a disease which is associated with plasma active GLP-I level in a mammal such as a human.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an SGLT inhibitor, a DPP4 inhibitor and a pharmaceutically acceptable carrier or diluent.
  • the pharmaceutical composition of the present invention can be used as an agent to lower a blood glucose level in a patient .
  • the pharmaceutical composition of the present invention can be used as an agent to increase plasma active GLP-I level in a patient .
  • the pharmaceutical composition of the present invention can be used as an agent for treatment or prevention of a disease which is associated with plasma active GLP-I level.
  • Examples of a disease which is associated with plasma active GLP-I level include diabetes, a condition related to diabetes, obesity, myocardial infarction, stroke, learning or memory impairment, and a neurodegenerative disorder.
  • Examples of a condition related to diabetes include hyperglycemia, impaired glucose tolerance, impaired fasting glucose, insulin resistance, pancreatic ⁇ -cell insufficiency, enteroendocrine cell insufficiency, glucosuria, metabolic acidosis, cataracts, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic coronary artery disease, diabetic cerebrovascular disease, diabetic peripheral vascular disease, metabolic syndrome, hyperlipidemia, atherosclerosis, hypertension, and obesity.
  • Examples of a neurodegenerative disorder include excito- toxic brain damage caused by severe epileptic seizures, Alzheimer's disease, Parkinson's disease, Huntington's disease, prion-associated disease, motor-neuron disease, traumatic brain injury, spinal cord injury, and peripheral neuropathy. Diabetes includes Type 1 or Type 2 diabetes.
  • the SGLT inhibitors and the DPP4 inhibitors may be administered to a patient by any conventional route of administration, including intravenous, oral, subcutaneous, intramuscular, intradermal and parenteral administration.
  • the SGLT inhibitors and the DPP4 inhibitors can be administered simultaneously, sequentially, or at separate intervals.
  • the SGLT inhibitor and the DPP4 inhibitor can be incorporated into a single pharmaceutical composition or into separate compositions.
  • therapeutically effective amounts of the SGLT inhibitor and the DPP4 inhibitor can be administered on a different schedule.
  • Each composition may be formulated with common excipients, diluents or carriers, and compressed into tablets, or formulated elixirs or solutions; and as sustained relief dosage forms and the like .
  • the SGLT inhibitor and the DPP4 inhibitor may be administered via different routes.
  • the SGLT inhibitor and the DPP4 inhibitor are provided in amounts to give a synergistic effect in increasing plasma active GLP-I level in a patient.
  • Optimal dose of the SGLT inhibitor and the DPP4 inhibitor will vary with patient's age, weight, sex, the particular compound used, the route of administration, and severity of the condition.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an SGLT inhibitor and DPP4 inhibitor, together with at least one pharmaceutically acceptable carrier or excipient.
  • the present invention relates to the use of an SGLT inhibitor and a DPP4 inhibitor for the manufacture of a medicament for the treatment or prevention of a disease associated with plasma active GLP-I level.
  • the present invention relates to the use of an SGLT inhibitor and a DPP4 inhibitor for the manufacture of a medicament for the treatment or prevention of diabetes .
  • the present invention relates to a product comprising an SGLT inhibitor and DPP4 inhibitor as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of a disease associated with plasma active GLP-I level.
  • the present invention relates to a product comprising a SGLT inhibitor and a DPP4 inhibitor as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of diabetes.
  • the pharmaceutical composition of the present invention is preferably in unit dosage forms such as tablets, capsules, powders, granules, solutions, suspen- sions, syrups, aerosol, and suppositories.
  • the pharmaceutical composition can be formulated with suitable pharmaceutically acceptable carriers and diluents.
  • suitable pharmaceutically acceptable carriers and diluents are available to those skilled in the art [see, e.g.,
  • Suitable carriers and diluents can include stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, magnesium carbonate, talc, gelatin, tragacanth, dextran sulfate sodium, sodium carboxymethylcellulose, methylcellulose, sodium alginate, pectin, dextrin, mannitol, sorbitol, lactose, sucrose, starch, cocoa butter, polyvinyl-pyrrolidone, polyvinyl alcohol, polyethylene glycols, propylene glycol, ethanol, corn oil, cottonseed oil, coconut oil, peanut oil, sesame oil, benzyl alcohol, and other pharmaceutically acceptable materials.
  • compositions may be prepared by methods well known to those skilled in the art, e.g., by means of conventional mixing, dissolving, granulation, levigation, emulsifying, encapsulation, entrapping, lyophilization or spray drying.
  • the SGLT inhibitor is a compound of Formula (23) or a pharmaceutically acceptable salt thereof, described above.
  • the SGLT inhibitor is a compound of Formula (24) or a pharmaceutically acceptable salt thereof, described above .
  • the SGLT inhibitor is a compound of Formula (25) or a pharmaceutically acceptable salt thereof, described above .
  • the SGLT inhibitor is a compound of Formula (26) or a pharmaceutically acceptable salt thereof, described above .
  • the SGLT inhibitor is Sergliflozin, Remogliflozin or Dapagliflozin, or a pharmaceutically acceptable salt thereof .
  • the DPP4 inhibitor is a compound of Formula (29) or a pharmaceutically acceptable salt thereof, described above.
  • the DPP4 inhibitor is a compound of Formula (30) or a pharmaceutically acceptable salt thereof, described above .
  • the DPP4 inhibitor is a compound of Formula (31) or a pharmaceutically acceptable salt thereof, described above .
  • the DPP4 inhibitor is Sitagliptin, Vildagliptin, Saxagliptin or Alogliptin, or a pharmaceutically acceptable salt thereof.
  • the SGLT inhibitor is Sergliflozin, Remogliflozin or Dapagliflozin, or a pharmaceutically acceptable salt thereof
  • the DPP4 inhibitor is Sitagliptin, Vildagliptin, Saxagliptin or Alogliptin, or a pharmaceutically acceptable salt thereof.
  • combination of the SGLT inhibitor and DPP4 inhibitor of the present invention include the following:
  • the SGLT inhibitor is a compound of Formula (23) :
  • Ring A and Ring B are one of the followings : (1) Ring A is optionally substituted unsaturated heteromono- cyclic, and Ring B is optionally substituted unsaturated heteromonocyclic, optionally substituted unsaturated fused heterobicyclic, or optionally substituted benzene, (2) Ring A is optionally substituted benzene, and Ring B is optionally substituted unsaturated heteromonocyclic, or optionally substituted unsaturated fused heterobicyclic wherein Y is linked to the heterocyclic ring of said fused heterobicyclic, or (3) Ring A is optionally substituted unsaturated fused heterobicyclic, wherein the sugar moiety X- (sugar) and the moiety -Y- (Ring B) are both on the same heterocyclic ring of said fused heterobicyclic, and Ring B is optionally substituted unsaturated heteromonocyclic, optionally substituted unsaturated fused heterobicyclic, or optionally substituted benzene; X
  • Y is - (CH 2 ) n- (wherein n is 1 or 2); or a pharmaceutically acceptable salt thereof, and the DPP4 inhibitor is a compound of formula (29) :
  • A represents -CH 2 - or -S-
  • R 1 represents hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group or a lower alkoxy lower alkyl group
  • R 2 represents (1) a cyclic group which may be substituted, where the cyclic group portion is (i) a monocyclic, bicyclic or tricyclic hydrocarbon group, or (ii) a monocyclic, bicyclic or tricyclic heterocyclic group, or (2) an amino group which may be substituted, or pharmaceutically acceptable slat thereof ; or the DPP4 inhibitor is a compound of Formula (31) : wherein :
  • X is -NR 1 R 2 wherein R 1 and R 2 may be the same or different and each is independently cycloalkylalkyl, arylalkyl, heteroaryl or heteroarylalkyl, or may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents, and the heterocycle optionally being a spiro ring,
  • R 3 and R 4 are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl or heteroarylalkyl, -NR 5 CONR 6 R 7 or -NR 5 CH 2 CH 2 NR 6 R 7 wherein R 5 , R 6 and R 7 are the same or different and each is independently hydrogen atom, alkyl, acyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or R 6 and R 7 may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents,
  • R 8 and R 9 are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or
  • Z is a hydrogen atom or cyano, and of the above-mentioned groups, alkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl and heterocycle each optionally have substituents, or a pharmaceutically acceptable salt thereof; or the DPP4 inhibitor is Sitagliptin or a pharmaceutically acceptable salt thereof;
  • the SGLT inhibitor is a compound of Formula (24)
  • R A is a halogen atom, or a lower alkyl group
  • Ring C is a phenyl group substituted by 1-3 substituents selected from the group consisting of a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group, a methyl- enedioxy group, an ethyleneoxy group, a mono- or di-lower alkylamino group, a carbamoyl group, and a mono- or di- lower alkylcarbamoyl group; or a heterocyclyl group substituted by 1-3 substituents selected from the group consisting of a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a halo- lower alkoxy group, a mono- or di-lower
  • X is -NR 1 R 2 wherein R 1 and R 2 may be the same or different and each is independently cycloalkylalkyl, arylalkyl, heteroaryl or heteroarylalkyl, or may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents, and the heterocycle optionally being a spiro ring,
  • R 3 and R 4 are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl or heteroarylalkyl,
  • R 5 , R 6 and R 7 are the same or different and each is independently hydrogen atom, alkyl, acyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or R s and R 7 may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents ,
  • R 1 is fluorine, or chlorine
  • R 2 is hydrogen, or fluorine, or a pharmaceutically acceptable salt thereof
  • the DPP4 inhibitor is a compound of formula (29) : wherein A represents -CH 2 - or -S-, R 1 represents hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group or a lower alkoxy lower alkyl group, and R 2 represents (1) a cyclic group which may be substituted, where the cyclic group portion is (i) a monocyclic, bicyclic or tricyclic hydrocarbon group, or (ii) a monocyclic, bicyclic or tricyclic heterocyclic group, or (2) an amino group which may be substituted, or a pharmaceutically acceptable slat thereof; or the DPP4 inhibitor is a compound of Formula (31) :
  • X is -NR 1 R 2 wherein R 1 and R 2 may be the same or different and each is independently cycloalkylalkyl, arylalkyl, heteroaryl or heteroarylalkyl, or may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents, and the heterocycle optionally being a spiro ring,
  • R 3 and R 4 are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl or heteroarylalkyl,
  • R 5 , R 6 and R 7 are the same or different and each is independently hydrogen atom, alkyl, acyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or R 6 and R 7 may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents,
  • the SGLT inhibitor is selected from:
  • Sitagliptin i.e., (3R) -3-amino-l- [3- (trifluoro- methyl) -5,6,7, 8-tetrahydro-5H- [1,2,4] triazolo [4, 3-a]pyra- zin-7-yl] -4- (2,4, 5-trifluorophenyl) butan-1-one
  • a pharmaceutically acceptable salt thereof e.g., phosphate
  • the dose can typically be selected from a range of about 0.01 to 100 mg/kg/day, preferably about 0.01 to 30 mg/kg/day.
  • the dose can typically be selected from a range of about 0.03 to 100 mg/kg/day, preferably about 0.03 to 30 mg/kg/day, more preferably about 0.03 to 10 mg/kg/day.
  • the dose can typically be selected from a range of about 0.01 to 30 mg/kg/day, preferably about 0.01 to 10 mg/kg/day, more preferably about 0.01 to 3 mg/kg/day.
  • the dose can typically be selected from a range of about 0.01 to 30 mg/kg/day, preferably about 0.01 to 10 mg/kg/day.
  • the dose can typically be selected from a range of about 0.03 to 30 mg/kg/day, preferably about 0.03 to 10 mg/kg/day, more preferably about 0.03 to 3 mg/kg/day.
  • the dose can typically be selected from a range of about 0.01 to 10 tng/kg/day, preferably about 0.01 to 3 mg/kg/day, more preferably about 0.01 to 1 mg/kg/day.
  • the dose ratio between the respective inhibitors can be selected appropriately, based on patient's age, weight, sex, severity of conditions, and route of administration.
  • the weight : weight dose ratio between the DPP4 inhibitor and the SGLT inhibitor may typically fall within a range of 1:0.01 to 1:600, preferably 1:0.1 to 1:300, more preferably 1:0.5 to 1:30.
  • both the SGLT inhibitor and the DPP4 inhibitor can be administered once or several times at the daily dose described above.
  • test compound was suspended in a solution of 0.5% carboxymethyl cellulose containing 0.2% Tween 80 at the doses indicated in Table 1, and administered to the test group orally at a volume of 5 mL/kg.
  • vehicle control group was orally administered a solution of 0.5% carboxy- methyl cellulose containing 0.2% Tween 80 at a volume of 5 mL/kg.
  • a glucose solution (2 g/kg/5 ml) was given orally.
  • Plasma active GLP-I level was determined by using RAT ENDOCRINE LINCOpIex KIT (LINCO Research) .
  • Each test compound was suspended in a solution of 0.5% carboxymethyl cellulose containing 0.2% Tween 80 at the doses indicated in Table 2, and administered to the test group orally at a volume of 5 mL/kg.
  • the vehicle control group was orally administered a solution of 0.5% carboxymethyl cellulose containing 0.2% Tween 80 at a volume of 5 mL/kg.
  • a glucose solution (2 g/kg/5 mL) was given orally.
  • Plasma Active GLP-I Level Blood was collected from the caudal vein of an unanesthetized rat just before and 0.2, 0.5, 1, and 2 hours after glucose loading. Plasma active GLP-I level was determined by using RAT ENDOCRINE LINCOplex KIT (LINCO Research) .
  • mice Male BKS-Cg-+ mice,- an Animal Model of Type 2 Diabetes (Purchased from CLEA Japan, Inc.)
  • Plasma active GLP-I level was determined by using RAT ENDOCRINE LINCOplex KIT (LINCO
  • Each test compound was suspended in a solution of 0.5% carboxymethyl cellulose containing 0.2% Tween 80 at the doses indicated in Table 4, 5 or 6, and administered to the test group orally at a volume of 5 mL/kg.
  • the vehicle control group was orally administered a solution of 0.5% carboxymethyl cellulose containing 0.2% Tween 80 at a volume of 5 mL/kg.
  • a glucose solution (2 g/kg/5 mL) was given orally.
  • Piasma active GLP-I level was determined by using RAT ENDOCRINE LINCOplex KIT (LINCO Research) .
  • a combination of an SGLT inhibitor and a DPP4 inhibitor can be used to prevent or treat some sort of disease which is associated with plasma active GLP-I level with a dose of a DPP4 inhibitor substantially lower than that currently contemplated for use in monotherapy for said condition, thereby reducing the likelihood of unwanted side-effects associated with inhibition of DPP4 activity.

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Abstract

The present invention relates to combination therapy comprising a DPP4 inhibitor and an SGLT inhibitor. The combination of the present invention leads to increase plasma GLP-1 level and the combination is useful for prevention or treatment of conditions such as diabetes and diseases related to diabetes.

Description

DESCRIPTION
COMBINATION THERAPY COMPRISING SGLT INHIBITORS AND DPP4 INHIBITORS
TECHNICAL FIELD
The present invention relates to compositions and methods for increasing plasma active GLP-I level in a mammal. The present invention further relates to compositions and methods for ameliorating conditions by increasing plasma active GLP-I level.
BACKGROUND ART
Glucagon-like peptide-1 (GLP-I) is an incretin hormone that is released from L-cells in lower small intestine after food intake. GLP-I has been shown to stimulate glucose-dependent insulin secretion from pancreatic β-cells and increase pancreatic β-cell mass. GLP-I has also been shown to reduce the rate of gastric emptying and promote satiety. However, GLP-I is rapidly cleaved by dipeptidyl peptidase 4 (DPP4) leading to inactivation of its biological activity. Therefore, DPP4 inhibitors are considered to be useful as anti-diabetics or anti-obesity agents.
Sodium-glucose co-transporters (SGLTs) , primarily found in the intestine and the kidney, are a family of proteins involved in glucose absorption. Plasma glucose is filtered in the glomerulus and is reabsorbed by SGLTs in the proximal tubules. Therefore, inhibition of SGLTs cause excretion of blood glucose into urine and leads to reduction of plasma glucose level. In fact, it is confirmed that by continuous subcutaneous administration of an SGLT inhibitor, phlorizin, to diabetic animal models, the blood glucose level thereof can be normalized, and that by keeping the blood glucose level normal for a long time, the insulin secretion and insulin resistance can be improved [cf., Journal of Clinical Investigation, vol. 79, p. 1510 (1987); ibid., vol. 80, p. 1037 (1987); ibid., vol. 87, p. 561 (1991) ] .
In addition, by treating diabetic animal models with an SGLT inhibitor for a long time, insulin secretion response and insulin sensitivity of the animal models are improved without incurring any adverse affects on the kidney or imbalance in blood levels of electrolytes, and as a result, the onset and progress of diabetic nephropathy and diabetic neuropathy are prevented [cf., Journal of Medicinal Chemistry, vol. 42, p. 5311 (1999); British Journal of Pharmacology, vol. 132, p. 578 (2001)].
In view of the above, SGLT inhibitors are expected to improve insulin secretion and insulin resistance by decreasing the blood glucose level in diabetic patients and to prevent the onset and progress of diabetes mellitus and diabetic complications.
DISCLOSURE OF INVENTION
The inventors of the present invention have found that administration of an SGLT inhibitor in combination with a DPP4 inhibitor can provide an unexpected synergistic effect in increasing plasma active GLP-I level in a patient over that provided by administration of the SGLT inhibitor or the DPP4 inhibitor alone.
Accordingly, in one aspect, the present invention relates to combination of an SGLT inhibitor and a DPP4 inhibitor such that the combination provides an effect in increasing plasma active GLP-I level in a patient over that provided by the SGLT inhibitor or the DPP4 inhibitor alone.
In another aspect, the present invention relates to use of combination of an SGLT inhibitor and DPP4 inhibitor for preventing or treating some sort of disease which is associated with plasma active GLP-I level.
In another aspect, the present invention relates to a pharmaceutical composition comprising an SGLT inhibitor and a DPP4 inhibitor for use in prevention or treatment of some sort of disease which is associated with plasma active GLP-
1 level .
In another aspect, the present invention relates to a method of preventing or treating some sort of disease which is associated with plasma active GLP-I level comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising an SGLT inhibitor and a DPP4 inhibitor.
In another aspect, the present invention relates to use of an SGLT inhibitor and a DPP4 inhibitor for the manufacture of a medicament for the prevention or treatment of some sort of disease which is associated with plasma active GLP-I level.
In another aspect, the present invention relates to a product containing an SGLT inhibitor and a DPP4 inhibitor as a combined preparation for simultaneous, separate or sequential administration for preventing or treating a disease associated with plasma active GLP-I level.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term "diabetes" encompasses both insulin-dependent diabetes mellitus (also known as Type 1 diabetes) and non-insulin-dependent diabetes mellitus (also known as Type 2 diabetes) .
The term "disease which is associated with plasma active GLP-I level" includes diabetes, a condition related to diabetes, obesity, myocardial infarction, stroke, learning impairment, memory impairment, and a neurodegenerative disorder.
The term "condition related to diabetes" includes hyperglycemia, impaired glucose tolerance, impaired fasting glucose, insulin resistance, pancreatic beta-cell insufficiency, enteroendocrine cell insufficiency, glucosuria, metabolic acidosis, cataracts, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic coronary artery disease, diabetic cerebrovascular disease, diabetic peripheral vascular disease, metabolic syndrome, hyperlipidemia, atherosclerosis, stroke, hypertension, and obesity.
The term "halogen" or "halo" refers to chlorine, bromine, fluorine and iodine, and chlorine and fluorine are preferable.
The term "alkyl" means a straight or branched saturated monovalent hydrocarbon chain having 1 to 12 carbon atoms, unless otherwise noted. The straight chain or branched chain alkyl group having 1 to 6 carbon atoms is preferable, and the straight chain or branched chain alkyl group having 1 to 4 carbon atoms is more preferable.
Examples of alkyl include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2, 2 , 4-trimethylpentyl, nonyl, decyl, and various branched chain isomers thereof. Further, the alkyl group may optionally and independently be substituted by 1 to 4 substituents as listed below, if necessary.
The term "alkylene" means a straight or branched divalent saturated hydrocarbon chain having 1 to 12 carbon atoms, unless otherwise noted. The straight chain or branched chain alkylene group having 1 to 6 carbon atoms is preferable, and the straight chain or branched chain alkylene group having 1 to 4 carbon atoms is more preferable. Examples of alkylene include methylene, ethylene, propylene, and trimethylene . If necessary, the alkylene group. may optionally be substituted similarly to "alkyl" as mentioned above.
When alkylene attaches at two different carbon atoms of the benzene ring, they form an annelated five, six or seven membered carbocycle together with the carbon atoms to which they are attached, and may optionally be substituted by one or more substituents defined below.
The term "alkenyl" means a straight or branched monovalent hydrocarbon chain having 2 to 12 carbon atoms and having at least one double bond, unless otherwise noted. Preferable "alkenyl" is a straight chain or branched chain alkenyl group having 2 to 6 carbon atoms, and the straight chain or branched chain alkenyl group having 2 to 4 carbon atoms is more preferable. Examples of alkenyl include vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3- pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, A- heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, A- dodecenyl, and 4, 8, 12-tetradecatrienyl . The alkenyl group may optionally and independently be substituted by 1 to 4 substituents as mentioned below, if necessary.
The term "alkenylene" means a straight or branched divalent hydrocarbon chain having 2 to 12 carbon atoms and having at least one double bond, unless otherwise noted. The straight chain or branched chain alkenylene group having 2 to 6 carbon atoms is preferable, and the straight chain or branched chain alkenylene group having 2 to 4 carbon atoms is more preferable. Examples of alkenylene include vinylene, propenylene, butadienylene . If necessary, the alkenylene group may optionally be substituted by 1 to 4 substituents as mentioned below, if necessary.
When an alkenylene group attaches at two different carbon atoms of a benzene ring, they form an annelated five, six or seven membered carbocycle (e.g., a fused benzene ring) together with the carbon atoms to which they are attached, and may optionally be substituted by one or more substituents defined below.
The term "alkynyl" means a straight or branched monovalent hydrocarbon chain having at least one triple bond, unless otherwise noted. The preferable alkynyl group is a straight chain or branched chain alkynyl group having 2 to 6 carbon atoms, and the straight chain or branched chain alkynyl group having 2 to 4 carbon atoms is more preferable. Examples of "alkynyl" include 2-propynyl, 3- butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3- hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3- nonynyl, 4-decynyl, 3-undecynyl, and 4-dodecynyl. The alkynyl group may optionally and independently be substituted by 1 to 4 substituents as mentioned below, if necessary.
The term "cycloalkyl" means a monocyclic or bicyclic monovalent saturated hydrocarbon ring having 3 to 12 carbon atoms, unless otherwise noted, and the monocyclic saturated hydrocarbon group having 3 to 7 carbon atoms is more preferable. "Examples of cycloalkyl include monocyclic and bicyclic alkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclodecyl. These groups may optionally and independently be substituted by 1 to 4 substituents as mentioned below, if necessary. The cycloalkyl group may optionally be condensed with a saturated hydrocarbon ring or an unsaturated hydrocarbon ring (said saturated hydrocarbon ring and unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO or SO2 within the ring, if necessary) , and the condensed saturated hydrocarbon ring and the condensed unsaturated hydrocarbon ring may be optionally and independently be substituted by 1 to 4 substituents as mentioned below.
The term "cycloalkylidene" means a monocyclic or bicyclic divalent saturated hydrocarbon ring having 3 to 12 carbon atoms, unless otherwise noted, and the monocyclic saturated hydrocarbon group having 3 to 6 carbon atoms is preferable. Examples of "cycloalkylidene" include monocyclic and bicyclic alkylidene such as cyclopropylidene, cyclobutylidene, cyclopentylidine, and eyelohexylidene . These groups may optionally and independently be substituted by 1 to 4 substituents as mentioned below, if necessary. Besides, the cycloalkylidene group may optionally be condensed with a saturated hydrocarbon ring or an unsaturated hydrocarbon ring (said saturated hydrocarbon ring and unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO or SO2 within the ring, if necessary) , and the condensed saturated hydrocarbon ring and the unsaturated hydrocarbon ring may be optionally and independently be substituted by 1 to 4 substituents as mentioned below.
The term "cycloalkenyl" means a monocyclic or bicyclic monovalent unsaturated hydrocarbon ring having 4 to 12 carbon atoms and having at least one double bond, unless otherwise noted. The preferable cycloalkenyl group is a monocyclic unsaturated hydrocarbon group having 4 to 7 carbon atoms. Examples of "cycloalkenyl" include monocyclic alkenyl such as cyclopentenyl, cyclopentadienyl, and cyclohexenyl . These groups may optionally and independently be substituted by 1 to 4 substituents as mentioned below, if necessary. Besides, the cycloalkenyl group may optionally be condensed with a saturated hydrocarbon ring or an unsaturated hydrocarbon ring (said saturated hydrocarbon ring and unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO or SO2 within the ring, if necessary) , and the condensed saturated hydrocarbon ring and the unsaturated hydrocarbon ring may be optionally and independently be substituted by 1 to 4 substituents as mentioned below.
The term "cycloalkynyl" means a monocyclic or bicyclic unsaturated hydrocarbon ring having 6 to 12 carbon atoms, and having at least one triple bond, unless otherwise noted. The preferable cycloalkynyl group is a monocyclic unsaturated hydrocarbon group having 6 to 8 carbon atoms. Examples of "cycloalkynyl" include monocyclic alkynyl such as cyclooctynyl, and cyclodecynyl . These groups may optionally be substituted by 1 to 4 substituents as mentioned below, if necessary. Besides, the cycloalkynyl group may optionally and independently be condensed with a saturated hydrocarbon ring or an unsaturated hydrocarbon ring (said saturated hydrocarbon ring and unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO or SO2 within the ring, if necessary) , and the condensed saturated hydrocarbon ring or the unsaturated hydrocarbon ring may be optionally and independently be substituted by 1 to 4 substituents as mentioned below.
The term "aryl" or "Aryl" means a monocyclic or bicyclic monovalent aromatic hydrocarbon group having 6 to 10 carbon atoms, unless otherwise noted. Examples of aryl include phenyl and naphthyl (including 1-naphthyl group and 2-naphthyl group) . These groups may optionally and independently be substituted by 1 to 4 substituents as mentioned below, if necessary. Besides, the aryl group may optionally be condensed with a saturated hydrocarbon ring or an unsaturated hydrocarbon ring (said saturated hydrocarbon ring and unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO or SO2 within the ring, if necessary) , and the condensed saturated hydrocarbon ring or the unsaturated hydrocarbon ring may be optionally and independently be substituted by 1 to 4 substituents as mentioned below.
The term "unsaturated monocyclic heterocyclic ring" means an unsaturated hydrocarbon ring containing 1-4 heteroatoms independently selected from a nitrogen atom, an oxygen atom and a sulfur atom, and the preferable one is a 4- to 7-membered saturated or unsaturated hydrocarbon ring containing 1-4 heteroatoms independently selected from a nitrogen atom, an oxygen atom and a sulfur atom, unless otherwise noted. Examples of the unsaturated monocyclic heterocyclic ring are pyridine, pyrimidine, pyrazine, furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, 4, 5-dihydrooxazolyl, thiazole, isothiazole, thiadiazole, triazole, and tetrazole . Among them, pyridine, pyrimidine, pyrazine, furan, thiophene, pyrrole, imidazole, oxazole, and thiazole can be preferably used. The unsaturated monocyclic heterocyclic ring may optionally and independ- ently be substituted by 1-4 substituents as mentioned below, if necessary.
The term "unsaturated fused heterobicyclic ring" means a hydrocarbon ring comprised of a saturated or a unsaturated hydrocarbon ring condensed with the above mentioned unsaturated monocyclic heterocyclic ring where said saturated hydrocarbon ring and said unsaturated hydrocarbon ring may optionally contain an oxygen atom, a nitrogen atom, a sulfur atom, SO, or SO2 within the ring, if necessary. Examples of the unsaturated fused heterobicyclic ring include benzothiophene, indole, tetrahydrobenzothiophene, benzofuran, isoquinoline, thienothiophene, thienopyridine, quinoline, indoline, isoindoline, benzothiazole, benzoxazole, indazole, and dihydroisoquinoline . Further, the "heterocyclic ring" also includes possible N- or S-oxides thereof.
The term "heterocyclyl" means a monovalent group of the above-mentioned unsaturated monocyclic heterocyclic ring or unsaturated fused heterobicyclic ring and a monovalent group of the saturated version of the above- mentioned unsaturated monocyclic heterocyclic or unsaturated fused heterobicyclic ring. If necessary, the heterocyclyl may optionally and independently be substituted by 1 to 4 substituents as mentioned below.
The term "alkanoyl" includes formyl and alkyl linked to carbonyl, unless otherwise noted.
The term "alkoxy" includes alkyl linked to oxygen, unless otherwise noted.
Examples of the substituent for the above each group includes halogen (e.g., fluorine, chlorine, bromine, and iodine) , nitro, cyano, oxo, hydroxy, mercapto, carboxyl, sulfo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyli- denemethyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkyloxy, cyclo- alkenyloxy, cycloalkynyloxy, aryloxy, heterocyclyloxy, alkanoyl, alkenylcarbonyl, alkynylcarbonyl, cycloalkyl- carbonyl, cycloalkenylcarbonyl, cycloalkynylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, alkoxycarbonyl , alkenyloxycarbonyl , alkynyloxycarbonyl , cycloalkyloxy- carbonyl, cycloalkenyloxycarbonyl, cycloalkynyloxycarbonyl, aryloxycarbonyl , heterocyclyloxycarbonyl, alkanoyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, cycloalkylcarbonyl- oxy, cycloalkenylcarbonyloxy, cycloalkynylcarbonyloxy, arylcarbonyloxy, heterocyclylcarbonyloxy, alkylthio, alkenylthio, alkynylthio, cycloalkylthio, cycloalkenylthio, cycloalkynylthio, arylthio, heterocyclylthio, amino, mono- or di-alkylamino, mono- or di-alkanoylamino, mono- or di- alkoxycarbonylamino, mono- or di-arylcarbonylamino, alkyl- sulfinylamino, alkylsulfonylamino, arylsulfinylamino, arylsulfonylamino, carbamoyl, mono- or di-alkylcarbamoyl, mono- or di-arylcarbamoyl, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, cycloalkylsulfinyl, cycloalkenylsulfinyl, eyeloalkynylsulfinyl, arylsulfinyl, heterocyclylsulfinyl, alkylsulfonyl, alkenylsulfonyl , alkynylsulfonyl, cycloalkylsulfonyl, cycloalkenylsulfonyl, cycloalkynylsulfonyl , arylsulfonyl, and heterocyclylsulfonyl . Each group mentioned above may optionally be substituted by these substituents.
Further, the terms such as haloalkyl, halo-lower alkyl, haloalkoxy, halo-lower alkoxy, halophenyl, and haloheterocyclyl mean alkyl, lower alkyl, alkoxy, lower alkoxy, phenyl group or heterocyclyl (hereinafter, referred to as "alkyl, etc.") being substituted by one or more halogen, respectively. Preferable examples include alkyl, etc., being substituted by 1 to 7 halogen, and more preferable examples include alkyl, etc., being substituted by 1 to 5 halogen. Similarly, the terms such as hydroxy- alkyl, hydroxy-lower alkyl, hydroxyalkoxy, hydroxy-lower alkoxy and hydroxyphenyl mean alkyl, etc., being substituted by one or more hydroxy groups. Preferable examples include alkyl, etc., being substituted by 1 to 4 hydroxy groups, and more preferable examples include alkyl., etc., being substituted by 1 to 2 hydroxy groups. Further, the terms such as alkoxyalkyl, lower alkoxyalkyl, alkoxy-lower alkyl, lower alkoxy-lower alkyl, alkoxyalkoxy, lower alkoxyalkoxy, alkoxy-lower alkoxy, lower alkoxy-lower alkoxy, alkoxyphenyl , and lower alkoxyphenyl means alkyl, etc., being substituted by one or more alkoxy groups.
Preferable examples include alkyl, etc., being substituted by 1 to 4 alkoxy groups, and more preferable examples include alkyl, etc., being substituted by 1 to 2 alkoxy groups .
The terms "arylakyl" and "arylalkoxy" as used alone or as part of another group refer to alkyl and alkoxy groups as described above having an aryl substituent.
The term "lower" used in the definitions for the formulae in the present specification means a straight or branched carbon chain having 1 to 6 carbon atoms, unless defined otherwise. More preferably, it means a straight or branched carbon chain having 1 to 4 carbon atoms .
The term "prodrug" means an ester or carbonate, which can be formed by reacting one or more hydroxy groups of the compound used in the combination therapy of the present invention with an acylating agent by a conventional method. Examples of the ester include acetate, pivalate, methyl- carbonate, and benzoate. Further, the term "prodrug" also means an ester or amide, which can be similarly formed by reacting one or more hydroxy groups of the compound used in the combination therapy of the present invention with an α-amino acid or a β-amino acid using a condensing agent by a conventional method.
Examples of a pharmaceutically acceptable salt of SGLT inhibitors or DPP4 inhibitors include a salt with an alkali metal (e.g., lithium, sodium, and potassium); a salt with an alkaline earth metal (e.g., calcium, and magnesium) ; a salt with zinc or aluminum,- a salt with an organic base (e.g., ammonia, choline, diethanolamine, lysine, ethylenediamine , t-butylamine, t-octylamine, tris (hydroxymethyl) aminomethane , N-methyl-glucosamine, triethanolamine and dehydroabietylamine) ; a salt with an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid); a salt with an organic acid (e.g., formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, and benzenesulfonic acid) ; and a salt with an acidic amino acid (e.g., aspartic acid, and glutamic acid) .
Additionally, the term "pharmaceutically acceptable salt" used herein encompass solvates, and hydrates thereof.
It is evident that some compounds used in the compositions or combination of the present invention may have one or more asymmetric carbon atoms in their structure. It is intended that the present invention includes within its scope the stereochemically pure isomeric forms of the compounds as well as their racemates . Stereochemically pure isomeric forms may be obtained by the methods well known to those skilled in the art. Diastereoisomers may be separated by physical separation methods such as fractional crystallization and chromatographic techniques, and enantiomers may be separated from each other by the selective crystallization of the diastereomeric salts with optically active acids or bases or by chiral chromatography. Pure stereoisomers may also be prepared synthetically from appropriate stereochemically pure starting materials, or by using stereospecific reactions.
SGLT inhibitors are well known to those skilled in the art, and examples of the SGLT inhibitors are described in many publications or patent literatures.
In an embodiment of the present invention, SGLT inhibitors are the C-aryl glucosides disclosed in WO 01/27128 pamphlet, which are represented by Formula (1) :
wherein:
R1, R2 and R2a are independently hydrogen, OH, OR5, alkyl, CF3, OCHF2, OCF3, SR5i or halogen, or two of R1, R2 and R2a together with the carbons to which they are attached can form an annelated five, six or seven membered carbocycle or heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, 0, S, SO, and/or SO2; R3 and R4 are independently hydrogen, OH, 0R5a, OAryl,
OCH2Aryl, alkyl, cycloalkyl, CF3, -OCHF2, -OCF3, halogen, -CN, -CO2R5b, -CO2H, -COR6b, -CH(OH)R60, -CH (0R5h) Rsd, -C0NR6Rδa, -NHC0R5c, -NHS02R5d, -NHS02Aryl, Aryl, -SR5e, -SOR5f, -S02R5g, -S02Aryl, or a five, six or seven membered heterocycle which may contain 1 to 4 heteroatoms in the ring which are
N, 0, S, SO, and/or SO2, or R3 and R4 together with the carbons to which they are attached form an annelated five, six or seven membered carbocycle or heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, 0, S, SO, and/or SO2;
R5, R5a, R5b, R5C, R5d, R5e, R5f, R5g, R5h and R5i are independently alkyl;
R5, RSa, Rεb, Rec and Rsd are independently hydrogen, alkyl, aryl, alkylaryl or cycloalkyl, or R6 and R5a together with the nitrogen to which they are attached form an annelated five, six or seven membered heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, 0, S, SO, and/or SO2;
A is 0, S, NH, or (CH2) n where n is 0-3, and a pharmaceu- tically acceptable salt thereof, all stereoisomers thereof, and all prodrug esters thereof.
In a preferable embodiment of the present invention, the SGLT inhibitor is Dapagliflozin represented by Formula (2) :
a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a prodrug ester thereof.
In another preferable embodiment of the present invention, the SGLT inhibitor is the C-aryl glucoside compound disclosed in WO 2006/034489 pamphlet, which is represented by Formula (3) :
a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a prodrug ester thereof.
In an embodiment of the present invention, the SGLT inhibitors are 0-aryl glucoside compounds disclosed in WO 01/74834 pamphlet, which are represented by Formula (4) :
wherein Y is
or heteroaryl ; R1, R2, R3, and R4 are the same or different and are independently selected from hydrogen, OH, OR7, lower alkyl, or halogen, or two of R1, R2, R3, and R4 together with the carbons to which they are attached can form an annelated five, six or seven membered carbocycle or heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO2;
R5 and R6 are the same or different and are independently selected from hydrogen, OH, 0R7a, -OAryl, -0CH2Aryl, lower alkyl, cycloalkyl, Aryl, arylalkyl, CF3, arylalkenyl, -OCHF2, -OCF3, halogen, -CN, -CO2R7b, -CO2H, COR8f, CHOHR8g, CH(OR7h)R8h, -CONR8R8a, -NHCOR70, -NHS02R7d, -NHS02Aryl, -SR7e, -SOR7f, -SO2R7g, -S02Aryl, -OCH2CO2R71, -OCH2CO2H, -OCH2CONR8bR8c, -OCH2CH2NR8dR8e, or a five, six or seven membered heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, 0, S, SO, and/or SO2, or R5 and R6 together with the carbons to which they are attached form an annelated five, six or seven membered carbocycle or heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, 0, S, SO, and/or SO2; R7, R7a, R7b, R7C, R7d, R7e, R7f, R7g, and R7i are independently lower alkyl; R8, R8a, R8b, R8c, R8d, R8e, R8f, R8g, and R8h are the same or different and are independently selected from hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, or together with the nitrogen to which they are attached form an annelated five, six or seven membered heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, 0, S, SO, and/or SO2; A is 0 (CH2) m, S, NH (CH2) m, or (CH2) n where n is 0-3 and m is 0-2, and a pharmaceutically acceptable salt thereof, all stereoisomers thereof, and all prodrug esters thereof.
In an embodiment of the present invention, the SGLT inhibitors are the glucopyranosyloxybenzylbenzene derivatives disclosed in WO 02/028872 pamphlet, which are represented by Formula (5) :
wherein P represents a group forming a prodrug; and R represents lower alkyl, lower alkoxy, lower alkylthio, lower alkoxy-substituted lower alkyl, lower alkoxy- substituted lower alkoxy or lower alkoxy-substituted lower alkylthio.
In an embodiment of the present invention, the SGLT inhibitors are the glucopyranosyloxybenzyl-benzene derivatives disclosed in WO 01/68660 pamphlet, which are represented by Formula (6) :
wherein R1 represents hydrogen or hydroxy (lower alkyl) ; and R2 represents lower alkyl, lower alkoxy, lower alkylthio, hydroxy (lower alkyl), hydroxy (lower alkoxy), hydroxy (lower alkylthio) , lower alkoxy-substituted (lower alkyl) , lower alkoxy-substituted (lower alkoxy) or lower alkoxy-substituted (lower alkylthio) , or a pharmaceutically acceptable salt thereof .
In a preferable embodiment of the present invention, the SGLT inhibitor is Sergliflozin represented by Formula (7) :
In another preferable embodiment of the present invention, the SGLT inhibitor is Sergliflozin-A represented by Formula (8) :
(B] In an embodiment of the present invention, the SGLT inhibitors are the glucopyranosyloxypyrazole derivatives disclosed in WO 02/053573 pamphlet, which are represented by Formula (9) :
wherein R represents hydrogen, lower alkyl or a group forming a prodrug,- one of Q and T represents a group represented by the formula:
(wherein P represents hydrogen or a group forming a prodrug) , while the other represents lower alkyl or halo (lower alkyl);
R2 represents hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halo (lower alkyl) or halogen; with the proviso that P does not represent hydrogen when R represents hydrogen or lower alkyl, or a pharmaceutically acceptable salt thereof .
In a preferable embodiment of the present invention, the SGLT inhibitor is Remogliflozin represented by Formula (9a) :
In an embodiment of the present invention, the SGLT inhibitors are the compounds disclosed in WO 2005/085265 pamphlet, which are represented by Formula (10) :
wherein one of R1 and R4 represents a group of the formula:
in which R5 and R6 independently represent hydrogen, hydroxy, halogen, Cλ-6 alkyl , C2-6 alkenyl, C2-6 alkynyl, Ci_s alkoxy, C2_s alkenyloxy, C1-6 alkylthio, C2-ε alkenylthio, halo (Ci-s alkyl), halo(Ci-e alkoxy), halo (C1-S alkylthio), hydroxy (C1-S alkyl) , hydroxy (C2-6 alkenyl) , hydroxy (C1-S alkoxy) , hydroxy (C1-S alkylthio) , carboxy, carboxy (C1-S alkyl) , carboxy (C2-S alkenyl) , carboxy (Cχ-S alkoxy) , carboxy(Ci-e alkylthio), C2_7 alkoxycarbonyl , C2-7 alkoxy- carbonyl (Ci_s alkyl), C2-7 alkoxycarbonyl (C2-s alkenyl), C2-7 alkoxycarbonyl (C1-S alkoxy), C2-7 alkoxycarbonyl (Ci-6 alkylthio), C1-S alky1sulfinyl, C1-S alkylsulfonyl, -U-V-W-N (R7) -Z, or any of the following substituents (i) to (xxviii) which may have 1 to 3 substituents selected from the following substituent group α on the ring,-
(i) Cs-io aryl, (ii) C6-10 aryl-O-, (iii) C6-I0 aryl-S-, (iv) Cs_10 aryl (C1-S alkyl) , (v) C6-I0 aryl (C1-S alkoxy) , (vi) C6-I0 aryl (C1-S alkylthio) , (vii) heteroaryl, (viii) heteroaryl-O- , (ix) heteroaryl-S-, (x) heteroaryl (C1-S alkyl), (xi) heteroaryl (C1-S alkoxy), (xii) heteroaryl (C1-S alkylthio), (xiii) C3-7 cycloalkyl, (xiv) C3.7 cycloalkyl-O- , (xv) C3-7 cycloalkyl-S- , (xvi) C3-7 cycloalkyl (C1-S alkyl), (xvii) C3_7 cycloalkyl (C1-S alkoxy), (xviii) C3.7 cycloalkyl (C1-S alkylthio), (xix) heterocycloalkyl, (xx) heterocycloalkyl- 0-, (xxi) heterocycloalkyl-S- , (xxii) heterocycloalkyl (C1-S alkyl), (xxiii) heterocycloalkyl (C1-S alkoxy), (xxiv) heterocycloalkyl (Ci-6 alkylthio), (xxv) aromatic cyclic amino, (xxvi) aromatic cyclic amino (C1-S alkyl), (xxvii) aromatic cyclic amino (Cχ-6 alkoxy), or (xxviii) aromatic cyclic amino (Ci-6 alkylthio),
J represents C1-S alkylene which may have hydroxy, or C2-ε alkenylene; U represents -O- , -S- or a single bond and with the proviso that at least one of V and W is not a single bond when U is -0- or -S-;
V represents C1-S alkylene which may have hydroxy, C2-ε alkenylene or a single bond; W represents -CO-, -SO2-, -C(=NH)- or a single bond;
Z independently represents hydrogen, C2-7 alkoxycarbonyl , Cs-io aryl(C2_7 alkoxycarbonyl), formyl, -RA, -CORB, -SO2RB, - CON(RC)RD, -CSN(RC)RD, -SO2NHRA or -C (=NRE) N (RF) RG; R7, RA, Rc and RD independently represent hydrogen, C1-S alkyl which may have 1 to 5 substituents selected from the following substituent group β, or any of the following substituents (xxix) to (xxxii) which may have 1 to 3 substituents selected from the following substituent group α,- (xxix) Cs-io aryl, (xxx) heteroaryl, (xxxi) C3-7 cycloalkyl or (xxxii) heterocycloalkyl or Z and R7 bind together with the neighboring nitrogen to form aliphatic cyclic amino which may have 1 to 3 substituents selected from the following substituent group α,- or Rc and RD bind together with the neighboring nitrogen to form aliphatic cyclic amino which may have 1 to 3 substituents selected from the following substituent group α; RB represents C2-7 alkoxycarbonyl, Ci_6 alkylsulfonylamino, Cε-io arylsulfonylamino, C1-S alkyl which may have 1 to 5 substituents selected from the following substituent group β or any of the following substituents (xxxiii) to (xxxvi) which may have 1 to 3 substituents selected from the following substituent group α,-
(xxxiii) Cs-io aryl, (xxxiv) heteroaryl, (xxxv) C3_7 cyclo- alkyl or (xxxvi) heterocycloalkyl, RE, RF and RG independently represent hydrogen, cyano, carbamoyl, C2-7 acyl, C2-7 alkoxycarbonyl, Cg-io aryl (C2-η alkoxycarbonyl) , nitro, C1-S alkylsulfonyl, sulfamide, carbamimidoyl or C1-S alkyl which may have 1 to 5 substituents selected from the following substituent group β; or RE and RF bind together to form ethylene; or RF and RG bind together with the neighboring nitrogen to form aliphatic cyclic amino which may have any substituent selected from the following substituent group α,- Q represents -C1-S alkylene-, -C2-s alkenylene-, -C2-e alkynylene-, -C1-S alkylene-O-, -Ci.ε alkylene-S-, -O-Ci-6 alkylene-, -S-C1-S alkylene-, -C1-S alkylene-O-Ci-6 alkylene-, -C1-S alkylene-S-Ci-s alkylene-, -CON(R8)-, -N(R8) CO-, -C1-S alkylene-CON (R8) - or -CON(R8) -C1-S alkylene-; R8 represents hydrogen or C1-S alkyl; ring A represents Ce-io aryl or heteroaryl, and the other one of R1 and R4 represents hydrogen, hydroxy, amino, halogen, C1-S alkyl, C1-S alkoxy, cyano, carboxy, C2-7 alkoxycarbonyl, carbamoyl, mono or di (C1^ alkyl) amino, halo (C1-S alkyl), hydroxy (C1-6 alkyl), cyano (C1-S alkyl), carboxy (Ci-6 alkyl), C2_7 alkoxycarbonyl (C1-S alkyl), carbamoyl (Ci-6 alkyl) group, an amino (Cχ-S alkyl) , mono or di(Ci_6 alkyl) amino (Ci-s alkyl), halo(Ci_6 alkoxy) , hydroxy- (C1.s alkoxy), carboxy(Ci-e alkoxy), C2-7 alkoxycarbonyl (Ci-S alkoxy), carbamoyl (Ci-e alkoxy), amino (Ci-6 alkoxy), mono or di (Ci-s alkyl) amino (Ci-6 alkoxy), C3-7 cycloalkyl, C3-7 cyclo- alkyloxy, C3-7 cycloalkyl (Ci-6 alkyl), or C3.7 cycloalkyl (Ci-s alkoxy) ,•
R2 and R3 independently represent hydrogen, hydroxy, amino, halogen, Ci-e alkyl, Ci-6 alkoxy, cyano, carboxy, C2-7 alkoxycarbonyl, carbamoyl, mono or di (Ci_6 alkyl) amino, halo (Ci-s alkyl), hydroxy (Ci_s alkyl), cyano (Ci_s alkyl), carboxy (Ci-ε alkyl), C2-7 alkoxycarbonyl (Ci-S alkyl), carbamoyl (Ci-s alkyl), amino (Ci_6 alkyl), mono or di (Ci-e alkyl) amino (Ci-6 alkyl), halo(Ci-6 alkoxy), hydroxy(Ci-6 alkoxy), carboxy (Ci_6 alkoxy), C2-7 alkoxycarbonyl (Ci_6 alkoxy), carbamoyl (Cx-e alkoxy), amino (Ci-6 alkoxy), mono or di(Ci-s alkyl) amino (Ci-s alkoxy), C3.7 cycloalkyl, C3_7 cycloalkyloxy, C3-7 cycloalkyl (Ci_e alkyl), or C3_7 cycloalkyl (Ci-s alkoxy) ; A1 represents 0, S or NR9; A2 represents CH or N,- R9 represents hydrogen or Ci_6 alkyl; G represents a group represented by a formula:
or a formula :
E1 represents hydrogen, fluorine or hydroxy; E2 represents hydrogen, fluorine, methyl or hydroxymethyl ; [substituent group α] halogen, hydroxy, amino, Ci.6 alkyl, Ci_6 alkoxy, halo (Ci.e alkyl) , halo (Ci.s alkoxy), hydroxy (Ci_6 alkyl), C2-? alkoxy- carbonyl (C1-S alkyl), hydroxy (Ci_6 alkoxy), amino (Cx-S alkyl), amino (Ci_s alkoxy), mono or di (Ci-s alkyl) amino, mono or di [hydroxy (Cx-S alkyl) ] amino, C1-S alkylsulfonyl, d_6 alkyl- sulfonylamino, Ci_6 alkylsulfonylatnino (Ci_6 alkyl), carboxy, C2-I alkoxycarbonyl , sulfamoyl and -CON (R11JR1 [substituent group β] halogen atom, hydroxy, amino, Ci-g alkoxy, Cx-6 alkylthio, halo (Ci_s alkoxy), halo (Ci.s alkylthio), hydroxy (Ci-6 alkoxy), hydroxy (C1-S alkylthio), amino (C1-S alkoxy), amino (C1-S alkylthio), mono or di (C1-S alkyl) amino, mono or di- [hydroxy (C1-S alkyl) ] amino, ureido, sulfamide, mono or di- (C1-S alkyl) ureido, mono or di [hydroxy (C1-S alkyl) ] ureido, mono or di (C1-S alkyl) sulfamide, mono or di [hydroxy (C1-6 alkyl) ] sulfamide, C2-7 acylamino, amino(C2-7 acylamino) , C1-S alkylsulfonyl, C1-S alkylsulfonylamino, carbamoyl (C1-S alkylsulfonylamino) , carboxy, C2-7 alkoxycarbonyl group, -CON(RH) R1, and any of the following substituents (xxxvii) to (xxxxviii) which may have 1 to 3 substituents selected from the above substituent group α,-
(xxxvii) C6.io aryl, (xxxviii) C6-I0 aryl-O-, (xxxix) C6-io aryl (C1-S alkoxy) , (xxxx) C6-I0 aryl (Ci_6 alkylthio) , (xxxxi) heteroaryl, (xxxxii) heteroaryl-O- , (xxxxiii) C3-7 cycloalkyl, (xxxxiv) C3.7 cycloalkyl-O- , (xxxxv) hetero- cycloalkyl, (xxxxvi) heterocycloalkyl-O- , (xxxxvii) aliphatic cyclic amino or (xxxxviii) aromatic cyclic amino RH and R1 independently represent hydrogen or C1-S alkyl which may have 1 to 3 substituents selected from the following substituent group γ,- or both of RH and R1 bind together with the neighboring nitrogen to form aliphatic cyclic amino which may have 1 to 3 substituents selected from the following substituent group δ ; [substituent group γ] halogen, hydroxy, amino, Ci_6 alkoxy, halo(Ci-5 alkoxy), hydroxy (Ci-6 alkoxy) , amino (Ci-6 alkoxy) , mono or di (C1-S alkyl) amino, mono or di [hydroxy (Cx_6 alkyl) ] amino, ureido, sulfamide, mono or di(Ci-6 alkyl) ureido, mono or di- [hydroxy (Ci-6 alkyl) ] ureido, mono or di(Ci_s alkyl) sulfamide, mono or di [hydroxy (Ci-S alkyl) ] sulfamide, C2-7 acylamino, amino (C2-7 acylamino), Ci-S alkylsulfonyl, Ci-6 alkylsulfon- ylamino, carbamoyl (Ci-s alkylsulfonylamino) , carboxy, C2-7 alkoxycarbonyl , sulfamoyl and -CON(RJ)RK
[substituent group δ] halogen, hydroxy, amino, Ci_6 alkyl, Ci_6 alkoxy, halo(Ci_6 alkyl), halo (C1-S alkoxy), hydroxy (C1-S alkyl), C2-7 alkoxycarbonyl (C1-S alkyl), hydroxy (C1-S alkoxy), amino (C1-S alkyl), amino (C1-S alkoxy), mono or di(Ci_6 alkyl) amino, mono or di [hydroxy (C1-S alkyl) ] amino, C1-S alkylsulfonyl, C1-S alkylsulfonylamino, Cα-6 alkylsulfonylamino (C1-S alkyl), carboxy, C2-? alkoxycarbonyl, sulfamoyl and -CON (RJ) Rκ RJ and Rκ independently represent hydrogen or C1-S alkyl which may have any 1 to 3 substituents selected from hydroxy, amino, mono or di (C1-S alkyl) amino, C2-7 alkoxy- carbonyl and carbamoyl; or both of RJ and Rκ bind together with the neighboring nitrogen to form aliphatic cyclic amino which may have any 1 to 3 substituents selected from hydroxy, amino, mono or di (C1-S alkyl) amino, C1-S alkyl, hydroxy (C1-S alkyl), C2-7 alkoxycarbonyl, C2-7 alkoxycarbonyl (C1-S alkyl) and carbamoyl, or a pharmaceutically acceptable salt thereof, or a prodrug thereof .
In an embodiment of the present invention, the SGLT inhibitors are the compounds disclosed in WO 2005/085267 pamphlet, which are represented by Formula (11) : wherein
R1 represents hydrogen, Ci-e alkyl, halo(Ci_6 alkyl) , hydroxy (Ci-6 alkyl) , dihydroxy (C1-S alkyl) , Ci-S alkoxy (C1-6 alkyl), C2-7 alkoxycarbonyl (C1-5 alkyl), carboxy(C1-s alkyl), C2-S alkenyl, -J-N(R5) -Z1, -J-CON (R5) -Z1, or any of the following substituents (a) to (d) which may have any 1 to 3 substituents selected from the following substituent group α on the ring,- (a) C3-7 cycloalkyl, (b) C3-7 cycloalkyl (C1-6 alkyl), (c) C6_10 aryl or (d) C1-S aryl (Cε_10 alkyl), R2 represents hydrogen, halogen or C1-6 alkyl; R3 and R4 independently represent hydrogen, hydroxy, halogen, Ci-e alkyl, C2-6 alkenyl, C2_6 alkynyl, C1-6 alkoxy, C2-6 alkenyloxy, C1-6 alkylthio, C2-6 alkenylthio, halo(Ci-S alkyl), 1IaIo(C1-S alkoxy), halo(Cχ-6 alkylthio), hydroxy(C1-6 alkyl), hydroxy (C2-6 alkenyl), hydroxy (Ci-e alkoxy), hydroxy- (C1-S alkylthio), carboxy, carboxy(Ci-6 alkyl), carboxy(C2_s alkenyl), carboxy (C1-6 alkoxy), carboxy (C1-S alkylthio), C2_7 alkoxycarbonyl, C2_7 alkoxycarbonyl (C1-S alkyl), C2-7 alkoxycarbonyl (C2-s alkenyl), C2_7 alkoxycarbonyl (C1-6 alkoxy), C2-7 alkoxycarbonyl (Ci-6 alkylthio), C1-S alkylsulfinyl, C1-6 alkylsulfonyl group, -U-V-W-N (Rs) -Z2, or any of the following substituents (i) to (xxviii) which may have any 1 to 3 substituents selected from the following substituent group α on the ring,-
(i) C6-I0 aryl, (ii) Cε-10 aryl-0-, (iii) C6-10 aryl-S-, (iv) C6-10 aryl (C1.6 alkyl), (v) C3-10 aryl(Ci_6 alkoxy), (vi) C6-10 aryl(Ci-6 alkylthio), (vii) heteroaryl, (viii) heteroaryl-O- , (ix) heteroaryl-S- , (x) heteroaryl (C1-6 alkyl), (xi) heteroaryl (C1-S alkoxy), (xii) heteroaryl (C1-6 alkylthio), (xiii) C3-7 cycloalkyl, (xiv) C3-7 cycloalkyl-O- , (xv) C3.7 cyclo- alkyl-S-, (xvi) C3-7 cycloalkyl (Ci-5 alkyl) , (xvii) C3-7 cycloalkyl (Ci-s alkoxy) , (xviii) C3-7 cycloalkyl (C1-S alkyl- thio) , (xix) heterocycloalkyl, (xx) heterocycloalkyl-O- , (xxi) heterocycloalkyl-S-, (xxii) heterocycloalkyl (Ci-6 alkyl), (xxiii) heterocycloalkyl (Ci_e alkoxy), (xxiv) heterocycloalkyl (C1-S alkylthio) , (xxv) aromatic cyclic amino, (xxvi) aromatic cyclic amino (Ci-S alkyl), (xxvii) aromatic cyclic amino (Ci-S alkoxy), or (xxviii) aromatic cyclic amino (Ci-6 alkylthio),
J represents C1-6 alkylene which may have hydroxy, or C2-s alkenylene;
U represents -0- , -S- or a single bond and with the proviso that at least one of V and W is not a single bond when U is -0-or -S-) ;
V represents Ci-6 alkylene which may have hydroxy, C2-s alkenylene or a single bond;
W represents -CO-, -SO2-, -C(=NH)- or a single bond,- Z1 and Z2 independently represent hydrogen, C2-7 alkoxy- carbonyl, C3-i0 aryl (C2-7 alkoxycarbonyl) , formyl, -RA, -C0RB, -SO2RB, -CON(RC)RD, -CSN(RC)RD, -SO2NHRA or -C (=NRE) N (RF) RG ; R5, R5, RA, Rc and RD independently represent hydrogen, C1-S alkyl which may have any 1 to 5 substituents selected from the following substituent group β or any of the following substituents (xxix) to (xxxii) which may have any 1 to 3 substituents selected from the following substituent group Ct;
(xxix) C6-I0 aryl, (xxx) heteroaryl, (xxxi) C3_7 cycloalkyl or (xxxii) heterocycloalkyl, or both of Z1 and R5 or both of Z2 and R6 bind together with the neighboring nitrogen to form aliphatic cyclic amino which may have any 1 to 3 substituents selected from the following substituent group α,- or Rc and RD bind together with the neighboring nitrogen to form aliphatic cyclic amino which may have any 1 to 3 substituents selected from the following substituent group α ;
RB represents C2_7 alkoxycarbonyl , Ci_ε alkylsulfonylamino, C6-Io arylsulfonylamino, C1.6 alkyl which may have any 1 to 5 substituents selected from the following substituent group β or any of the following substituents (xxxiii) to (xxxvi) which may have any 1 to 3 substituents selected from the following substituent group α,-
(xxxiii) C6-Io aryl, (xxxiv) heteroaryl, (xxxv) C3_7 cyclo- alkyl or (xxxvi) heterocycloalkyl, RE, RF and RG independently represent hydrogen, cyano, carbamoyl, C2-7 acyl group, C2_7 alkoxycarbonyl, Cs_i0 aryl (C2- 7 alkoxycarbonyl), nitro, C±-6 alkylsulfonyl, sulfamoyl, carbamimidoyl or Ci_e alkyl which may have any 1 to 5 substituents selected from the following substituent group β; or RE and RF bind together to form ethylene; or RF and RG bind together with the neighboring nitrogen to form aliphatic cyclic amino which may have a substituent selected from the following substituent group α,- Y represents CH or N;
Q represents -C1.6 alkylene-, -C2-e alkenylene-, -C2-e alkynylene-, -Ci_6 alkylene-O-, -Ci-6 alkylene-S-, -O-Cχ_6 alkylene-, -S-Cx-g alkylene-, -C1-S alkylene-0-Cχ-e alkylene-, -C1-S alkylene-S-Ci-e alkylene-, -CON(R7)-, -N (R7) CO-, -C1-S alkylene-CON(R7) - or -CON (R7) -C1-S alkylene-; R7 represents hydrogen or Ci-S alkyl; ring A represents C6-10 aryl or heteroaryl; G represents a group represented by a formula:
or a formula
E1 represents hydrogen, fluorine or hydroxy,- E2 represents hydrogen, fluorine, methyl or hydroxymethyl ; [substituent group α] halogen, hydroxy, amino, Ci.6 alkyl, C1-S alkoxy, halo(Ci_6 alkyl) , a halo(Ci-s alkoxy), hydroxy (Ci-6 alkyl), C2-η alkoxycarbonyl (Ci-6 alkyl), hydroxy (Ci_6 alkoxy), amino (C1-S alkyl), amino (Ci-6 alkoxy), mono or di (C1-S alkyl) amino, mono or di [hydroxy (C1-S alkyl) ] amino, Ci_6 alkylsulfonyl, C1-6 alkyl- sulfonylamino, C1-S alkylsulfonylamino (C1-S alkyl), carboxy, C2-7 alkoxycarbonyl , sulfamoyl and -CON (R11JR1
[substituent group β] halogen, hydroxy, amino, C1-S alkoxy, C1-S alkylthio, halo(C1_6 alkoxy), halo(Ci-6 alkylthio) , hydroxy (Ci_6 alkoxy), hydroxy (C1-S alkylthio) , amino (C1-S alkoxy), amino (C1-S alkylthio) , mono or di (C1-S alkyl) amino, mono or di [hydroxy (C1-S alkyi) ] amino, ureido, sulfamide, mono or di (C1-S alkyl) ureido, mono or di [hydroxy (C1-S alkyl) ] ureido, mono or di (C1-S alkyl) sulfamide, mono or di [hydroxy (C1-S alkyl) ]- sulfamide, C2-7 acylamino, amino (C2-7 acylamino) , Ci_6 alkylsulfonyl, Ci_6 alkylsulfonylamino, carbamoyl (C1-S alkylsulfonylamino) , carboxy, C2-7 alkoxycarbonyl, -CON(RH) R1, and any of the following substituents (xxxvii) to (xxxxviii) which may have any 1 to 3 substituents selected from the above substituent group α on the ring,-
(xxxvii) Cs-io aryl, (xxxviii) C6-:LO aryl-O-, (xxxix) C6-ILo aryl (C1-S alkoxy), (xxxx) C6_10 aryl (C1-S alkylthio) , (xxxxi) heteroaryl, (xxxxii) heteroaryl-O- , (xxxxiii) C3_7 cycl- oalkyl, (xxxxiv) C3-7 cycloalkyl-O- , (xxxxv) heterocyclo- alkyl, (xxxxvi) heterocycloalkyl-O- , (xxxxvii) aliphatic cyclic amino or (xxxxviii) aromatic cyclic amino RH and R1 independently represent hydrogen or C1-S alkyl which may have any 1 to 3 substituents selected from the following substituent group γ,- or both of RH and R1 bind together with the neighboring nitrogen to form aliphatic cyclic amino which may have any 1 to 3 substituents selected from the following substituent group δ;
[substituent group γ] halogen, hydroxy, amino, Ci_6 alkoxy, halo(Ci_5 alkoxy) , hydroxy (Ci-s alkoxy), amino (C1-S alkoxy), mono or di (Ci-S alkyl) amino, mono or di [hydroxy (Ci_6 alkyl) ] amino, ureido, sulfamide, mono or di(Ci-s alkyl) ureido, mono or di [hydroxy (Ci-6 alkyl) ] ureido, mono or di (Ci-S alkyl) sulfamide, mono or di [hydroxy (Ci-6 alkyl) ] sulfamide, C2-7 acylamino, amino (C2-7 acylamino) , C1-5 alkylsulfonyl, Ci-6 alkylsulfonylamino, carbamoyl (Ci-6 alkylsulfonylamino) , carboxy, C2-7 alkoxy- carbonyl and -CON(RJ)RK
[substituent group δ] halogen, hydroxy, amino, Ci_6 alkyl, Ci_s alkoxy, halo(Ci_s alkyl), halo (Ci-e alkoxy), hydroxy (Ci_s alkyl), C2-7 alkoxy- carbonyl (Ci-6 alkyl), hydroxy (Cx-S alkoxy), amino (Ci-6 alkyl), amino (Ci-6 alkoxy), mono or di(Ci.s alkyl) amino, mono or di [hydroxy (Ci-s alkyl)] amino, Cx-S alkylsulfonyl, Ci_s alkylsulfonylamino, Ci-s alkylsulfonylamino (Ci-ε alkyl), carboxy, C2-7 alkoxycarbonyl , sulfamoyl and -CON(RJ)RK
RJ and Rκ independently represent hydrogen or Ci-S alkyl which may have any 1 to 3 substituents selected from hydroxy, amino, mono or di(Ci-s alkyl) amino, C2-7 alkoxycarbonyl and carbamoyl ; or both of Rσ and Rκ bind together with the neighboring nitrogen to form aliphatic cyclic amino which may have any 1 to 3 substituents selected from hydroxy, amino, mono or di(Ci_s alkyl) amino, C1-S alkyl, hydroxy (Ci-S alkyl), C2.7 alkoxycarbonyl, C2_7 alkoxycarbonyl (Ci_6 alkyl) and carbamoyl, or a pharmaceutically acceptable salt thereof, or a prodrug thereof . In an embodiment of the present invention, the SGLT inhibitors are the glucopyranosyloxypyrazole derivatives disclosed in WO 01/16147 pamphlet, which are represented by Formula (12) :
wherein R1 represents hydrogen or lower alkyl ; one of Q1 and T1 represents a group represented by the formula:
while the other represents lower alkyl or halo (lower alkyl) ,- and R2 represents hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halo (lower alkyl) or halogen, or a pharmaceutically acceptable salt thereof.
In an embodiment of the present invention, the SGLT inhibitors are the compounds disclosed in WO 2006/035796 pamphlet, which are represented by Formula (13) :
wherein Ring A represents aryl or heteroaryl, each of which may have a substituent (s) , Q1 to Q5 are each independently carbon to which hydrogen or a substituent is connected, or nitrogen, E represents a single bond, alkylene, -0-, -S- or -NH-, and R represents methyl, ethyl, fluoromethyl or hydroxymethyl , or a prodrug thereof or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.
In an embodiment of the present invention, the SGLT inhibitors are the azulene derivatives disclosed in WO 2004/013118 pamphlet, which are represented by Formula (14) :
wherein R1 to R4 individually represent hydrogen, optionally substituted lower alkyl, -C (=0) -optionally substituted lower alkyl, or -optionally substituted lower alkylene- optionally substituted aryl, R5 to R12 individually represent hydrogen, optionally substituted lower alkyl, halogen, -OH, -O-optionally substituted lower alkyl, -optionally substituted lower alkylene-OH, -optionally substituted lower alkylene-O- optionally substituted lower alkyl, -O-optionally substituted lower alkylene-O-optionally substituted lower alkyl, -O-optionally substituted lower alkylene-optionally substituted aryl, -optionally substituted lower alkylene-O- C (=0) -optionally substituted lower alkyl, -COOH, nitro, cyano, amino, substituted amino, or -C (=0) -O-optionally substituted lower alkyl, and A represents bond or optionally substituted lower alkylene, wherein -A- may be bonded to any one of the positions 1-8 of the azulene ring, and any two of Rs, R6, and R7 may form a benzene ring together with the adjacent carbon atoms.
In still another embodiment of the present invention, the SGLT inhibitors are the compounds disclosed in WO 2004/080990 pamphlet, which are represented by Formula (15) :
wherein A ring represents (1) benzene, (2) five or six- membered monocyclic heteroaryl having 1 to 4 hetero atom(s) selected from N, S, and 0, or (3) saturated or unsaturated eight to ten-membered heterobicyclic having 1 to 4 hetero atom(s) selected from N, S, and 0; B ring represents (1) saturated or unsaturated eight to ten-membered heterobicyclic having 1 to 4 hetero atom(s) selected from N, S, and 0, (2) saturated or unsaturated five or six-membered heteromonocyclic having 1 to 4 hetero atom(s) selected from N, S, and O, (3) a saturated or an unsaturated eight to ten-membered bicyclic hydrocarbon, or (4) benzene;
X represents bond or lower alkylene,- wherein Ring A, Ring B, and X have a correlation that (1) when Ring A is benzene, Ring B is a ring other than benzene or that (2) when Ring A is benzene, and Ring B is saturated or unsaturated eight to ten-membered heterobicyclic having 1 to 4 hetero atom(s) selected from N, S, and 0 including benzene, or saturated or unsaturated eight to ten-membered bicyclic hydrocarbon including benzene, X is bonded to Ring B in a part other than the benzene ring included in Ring B : incidentally, this correlation specifically means that Ring A and Ring B cannot be benzene simultaneously and that when Ring A is benzene and Ring B is benzofuran or indane, X is not benzene constituting a part of Ring B but bonds with furan or cyclopentane; R1 to R4 individually represent hydrogen, lower alkyl, -C (=0) -lower alkyl, or -lower alkylene-aryl; and R5 to R11 individually represent hydrogen, lower alkyl, cycloalkyl, halogen, halogen-substituted lower alkyl, -OH, =0, -NH2, lower alkylsulfonyl- , halogen-substituted lower alkylsulfonyl- , aryl sulfonyl-, aryl, saturated or unsaturated five or six-membered heteromonocyclic having 1 to 4 hetero atom(s) selected from N, S, and 0, -lower alkylene-OH, -lower alkylene-O-lower alkyl, -lower alkylene-O-C (=0) -lower alkyl, -lower alkylene-O-lower alkylene-COOH, -lower alkylene-O-lower alkylene-C (=0) -0- lower alkyl, -lower alkylene-NH2, -lower alkylene-NH-lower alkyl', -lower alkylene-N (lower alkyl) 2, -lower alkylene-NH- C (=0) -lower alkyl, -COOH, -CN, -C (=0) -0-lower alkyl, -C(=O)-NH2, -C (=0) -NH-lower alkyl, -C (=0) -N (lower alkyl) 2, -0-lower alkyl, -0-cycloalkyl, -0-lower alkylene-OH, -0- lower alkylene-O-lower alkyl, -0-lower alkylene-COOH, -0- lower alkylene-C (=0) -0-lower alkyl, -0-lower alkylene- C(=O)-NH2, -0-lower alkylene-C (=0) -NH-lower alkyl, -0-lower alkylene-C (=0) -N (lower alkyl)2, -0-lower alkylene-CH (OH) - CH2(OH), -0-lower alkylene-NH2, -0-lower alkylene-NH-lower alkyl, -0-lower alkylene-N (lower alkyi)2, -0-lower alkylene-NH-C (=0) -lower alkyl, -NH-lower alkyl, -N(lower alkyl) 2, -NH-S02-lower alkyl, -NH-S02-halogen-substituted lower alkyl, -NH-lower alkylene-OH, -NH-C (=0) -lower alkyl, -NH-C (=0) -NH2, -NH-C (=0) -NH-lower alkyl , -NH-C (=0) -N (lower alkyl) 2, or -NH-C (=0) -0-lower alkyl.
In a preferable embodiment of the present invention, the SGLT inhibitors are represented by Formula (15a) :
wherein: Rε represents a hydrogen atom, halogen atom, -OH, -OMe, -CH2-OH, -O- (CH2) 2-OH, -O- (CH2) 2-NH2, -COOH, -COOEt, -0-CH2-COOH, or -0-CH2-COOEt, R7 represents a hydrogen atom or halogen atom, R8 represents a hydrogen atom, or -Me, and R9 represents a hydrogen atom, -Me, halogen atom, or -OMe.
In an embodiment of the present invention, the SGLT inhibitors are the glucopyranosyl-substituted benzene derivatives disclosed in WO 2005/092877 pamphlet, which are represented by Formula (16) :
wherein R1 is selected from the definitions of the group A, and if R3 is selected from the definitions of the group B, R1 may additionally be selected from hydrogen, fluorine, chlorine, bromine, iodine, C3.-4 alkyl, C2_4 aikenyl-Ci_4 alkyl, C2-4 alkynyl-Ci-4 alkyl, C2.4 alkenyl-C^ alkoxy, C2-4 alkynyl- C1-4 alkoxy, C3_7 cycloalkyl-Ci-4 alkyl, C5-7 cycloalkenyl-Ci-4 alkyl, methyl substituted by 1 to 3 fluorine, ethyl substituted by 1 to 5 fluorine, C1-4 alkoxy, methoxy substituted by 1 to 3 fluorine, ethoxy substituted by 1 to 5 fluorine, C1-4 alkyl substituted by hydroxy or C1.3 alkoxy, C2-4 alkoxy substituted by hydroxy or C1-3 alkoxy, C3-6 cycloalkyl-Ci-3 alkoxy or hydroxy, while in the above- mentioned cycloalkyl and cycloalkenyl rings one or two methylene groups may be replaced independently of one another by 0 or CO;
R2 denotes hydrogen, fluorine, chlorine, bromine, hydroxy, Ci-4 alkyl, Ci-4 alkoxy, cyano or nitro, while the alkyl or alkoxy group may be mono- or polysubstituted by fluorine; R3 is selected from the definitions of the group B, and if R1 is selected from the definitions of the group A, R3 may additionally be selected from the meanings hydrogen, fluorine, chlorine, bromine, iodine, Cx-6 alkyl, C2.4 alkenyl-Ci-4 alkyl, C2-4 alkynyl-Ci-4 alkyl, C2.4 alkenyl-Cx-4 alkoxy, C2-4 alkynyl-Ci-4 alkoxy, C3-7 cycloalkyl, C5-7 cyclo- alkenyl, C3_7 cycloalkyl-Ci-4 alkyl, C5-7 cycloalkenyl-Ci-4 alkyl, C3-s cycloalkylidenemethyl, hydroxy, Ci-6 alkoxy, C3_e cycloalkyl-Ci-3 alkoxy, aryl, aryl-Cx_3 alkyl, heteroaryl, heteroaryl-Ci_3 alkyl, aryloxy, aryl-Ci-3 alkyl-oxy, methyl or methoxy substituted by 1 to 3 fluorine, C2_4 alkyl or C2-4 alkoxy substituted by 1 to 5 fluorine, C1-4 alkyl substituted by cyano, C1-4 alkyl substituted by hydroxy or Ci-3 alkyloxy, cyano, carboxy, Cx-3 alkoxycarbonyl , aminocarbonyl , (Ci_3 alkylamino) carbonyl, di- (Ci_3 alkyl) aminocarbonyl, pyrrolidin-1-ylcarbonyl , piperidin-1-ylcarbonyl, morpholin- 4-ylcarbonyl, piperazin-1-ylcarbonyl, 4- (Cx-3 alkyl) - piperazin-1-ylcarbonyl, (Ci-4 alkyl) carbonylamino, Ci-4 alkyl-sulfonylamino, Cx-4 alkylsulfanyl, Ci-4 alkylsulfinyl, Ci_4 alkylsulfonyl, arylsulfonylamino, aryl-Ci-3 alkylsulfon- ylamino or arylsulfonyl ;
R4 and R5 independently of one another denote hydrogen, fluorine, chlorine, bromine, iodine, cyano, nitro, Cx-3 alkyl, Cx-3 alkoxy, or methyl or methoxy substituted by 1 to 3 fluorine, A denotes C2-6 alkyn-1-yl, C2-6 alken-1-yl, C3.7 cycloalkyl, C5_7 cycloalkenyl, aryl, heteroaryl, Cx-4 alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aminocarbonyl, Cx-4 alkyl- aminocarbonyl, di-(Cx-3 alkyl) aminocarbonyl , pyrrolidin-1- ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, 4- (C1-4 alkyl) piperazin-1-ylcarbonyl, arylamino-carbonyl, heteroarylaminocarbonyl, Cx-4 alkoxycarbonyl, aryl-C1-3 alkoxycarbonyl, heteroaryl-Cx_3 alkoxycarbonyl, amino, Cx-4 alkylamino, di- (Cx-3 alkyl) amino, pyrrolidin-1-yl, pyrrolidin-2-on-l-yl, piperidin-l-yl, piperidin-2-on-l-yl, morpholin-4-yl, morpholin-3-on-4-yl, piperazin-1-yl, 4- (Cx-3 alkyl) piperazin-1-yl, Cx-4 alkyl- carbonylamino, arylcarbonylamino, heteroarylcarbonylamino, C3.7 cycloalkyloxy, C5-7 cycloalkenyloxy, aryloxy, hetero- aryloxy, Ci_4 alkylsulfinyl, Ci-4 alkylsulfonyl, C3-7 cyclo- alkylsulfanyl, C3.7 cycloalkylsulfinyl, C3.7 cycloalkyl- sulfonyl, C5.7 cycloalkenylsulfanyl, C5.7 cycloalkenyl- sulfinyl, C5.7 cycloalkenylsulfonyl, arylsulfanyl, aryl- sulfinyl, arylsulfonyl, heteroarylsulfanyl, heteroaryl- sulfinyl, heteroarylsulfonyl, cyano or nitro, while the above-mentioned alkynyl and alkenyl groups may be mono- or polysubstituted by fluorine or chlorine, and the above- mentioned alkynyl and alkenyl groups may be mono- or di- substituted by identical or different groups L1, and the above-mentioned cycloalkyl and cycloalkenyl rings independently of one another may be mono- or di-substituted by substituents selected from fluorine and Ci.3 alkyl, and in the above-mentioned cycloalkyl and cycloalkenyl rings one or two methylene groups may be replaced independently of one another by 0, S, CO, SO, SO2 or NRN; B denotes tri- (Ci-4 alkyl) silyl-Ci_ε alkyl, C2-β alkyn-1-yl, C2-e alken-1-yl, amino, Ci_3 alkylamino, di- (Ci-3 alkyl) amino, pyrrolidin-1-yl, pyrrolidin-2-on-l-yl, piperidin-1-yl, piperidin-2-on-l-yl, morpholin-4-yl, morpholin-3-on-4-yl, piperazin-1-yl, 4- (Ci-3 alkyl)piperazin-l-yl, arylcarbonylamino, heteroarylcarbonylamino, nitro, C3-I0 cycloalkyloxy, C5-10 cycloalkenyloxy, C3-I0 cycloalkylsulfanyl , C3.10 cycloalkylsulfinyl, C3-I0 cycloalkylsulfonyl, C5-I0 cycloalkenylsulfanyl, C5-I0 cycloalkenylsulfinyl, C5-I0 cycloalkenylsulfonyl, arylsulfanyl, arylsulfinyl, heteroarylsulfanyl or heteroarylsulfinyl, while the above-mentioned alkynyl and alkenyl groups may be mono- or polysubstituted by fluorine or chlorine, and the above-mentioned alkynyl and alkenyl groups may be mono- or di-substituted by identical or different groups L1; while the above-mentioned cycloalkyl and cycloalkenyl rings may be mono- or di-substituted independently of one another by substituents selected from fluorine and Cx-3 alkyl, and in the above-mentioned cycloalkyl and cycloalkenyl rings one or two methylene groups may be replaced independently of one another by 0, S, CO, SO, SO2 or NRN;
RN denotes H, Ci_4 alkyl, Ci-4 alkylcarbonyl or Ci-4 alkyl- sulfonyl,
L1 independently of one another is selected from hydroxy, cyano, nitro, C3-7 cycloalkyl, aryl, heteroaryl, C1^4 alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aminocarbonyl , Ci-4 alkylaminocarbonyl, di- (Ci_3 alkyl) -aminocarbonyl , pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin- 4-ylcarbonyl, arylaminocarbonyl , heteroarylaminocarbonyl , Ci-4 alkoxycarbonyl, aryl-C1.3 alkoxycarbonyl , heteroaryl-C1-3 alkoxycarbonyl , C1-4 alkyloxy, aryloxy, heteroaryloxy, Cχ_4 alkylsulfanyl, arylsulfanyl, heteroarylsulfanyl, Ci-4 alkyl- sulfinyl, arylsulfinyl, heteroarylsulfinyl, Ci_4 alkylsulfonyl, arylsulfonyl and heteroarylsulfonyl; L2 independently of one another is selected from fluorine, chlorine, bromine, iodine, Cx-3 alkyl, difluoromethyl, trifluoromethyl, Ci-3 alkoxy, difluoromethoxy, trifluoro- methoxy and cyano;
Rs, R7a, R7b, and R7c independently of one another have a meaning selected from hydrogen, (C1-I8-alkyl) carbonyl, (C1- i8-alkyl) oxycarbonyl, arylcarbonyl and aryl- (C1^3 alkyl) - carbonyl, while the aryl group mentioned in the definition of the above groups are meant phenyl or naphthyl group which may be mono- or di-substituted independently of one another by identical or different groups L2; and the heteroaryl group mentioned in the definition of the above groups are meant a pyrrolyl, furanyl, thienyl, pyridyl, indolyl, benzofuranyl , benzothiophenyl, quinolinyl, isoquinolinyl or tetrazolyl group, or is meant pyrrolyl, furanyl, thienyl or pyridyl, wherein one or two methyne groups are replaced by nitrogen, or is meant indolyl, benzofuranyl , benzothiophenyl, quinolinyl or isoquinolinyl, wherein one to three methyne groups are replaced by nitrogen, while the above-mentioned heteroaryl groups independently of one another may be mono- or di-substituted by identical or different groups L2; while, unless otherwise stated, the above-mentioned alkyl group may be straight-chain or branched, the tautomers, the stereo- isomers thereof, the mixtures thereof and the salts thereof.
In a preferable embodiment of the present invention, the SGLT inhibitor is the compound disclosed in WO 2006/117359 pamphlet, which is represented by Formula (17) :
In another preferable embodiment of the present invention, the SGLT inhibitor is the compound disclosed in WO 2006/117360 pamphlet, which is represented by Formula (18) :
In an embodiment of the present invention, the SGLT inhibitors are the propiophenone derivatives disclosed in U.S. Pat. No. 6,048,842, or a pharmaceutically acceptable salt thereof, which are represented by Formula (19) : wherein OX is a hydroxy group which may optionally be protected, Y is a lower alkyl group, and Z is a β-D-gluco- pyranosyl group wherein one or more hydroxy groups may optionally be protected.
In an embodiment of the present invention, the SGLT inhibitors are the propiophenone derivatives disclosed in U.S. Pat. No. 5,830,873, or a pharmaceutically acceptable salt thereof, which are represented by Formula (20) :
wherein X is an oxygen atom, a sulfur atom or a methylene group, OY is a protected or unprotected hydroxy group, Z is a β-D-glucopyranosyl group or 4-0- (α-D-glucopyranosyl) -β-D- glucopyranosyl group wherein one or more hydroxy groups of these groups may optionally be acylated, and the dotted line means the presence or absence of a double bond.
In an embodiment of the present invention, the SGLT inhibitors are the propiophenone derivatives or a pharmaceutically acceptable salt thereof, disclosed in U.S. Pat No. 5,767,094, which are represented by Formula (21) : wherein R1 is a lower alkanoyl group, and R" is a hydrogen atom, or R1 is a hydrogen atom, and R" is a lower alkoxy- carbonyl group .
In an embodiment of the present invention, the SGLT inhibitor is the propiophenone derivatives or a pharmaceutically acceptable salt thereof disclosed in U.S. Pat. Nos . 5,424,406 and 5,731,292, which are represented by Formula (22) :
wherein Ar is an aryl group, R1 is hydrogen atom or an acyl group, R2 is hydrogen atom, an acyl group or α-D-gluco- pyranosyl group, or R1 and R2 may combine together to form a substituted methylene group, R3 and R4 are each hydrogen atom or an acyl group, and OR5 is a protected or unprotected hydroxy group or a lower alkoxy group .
In an embodiment of the present invention, the SGLT inhibitors are the compounds disclosed in United States
Patent Application Publication No. 2005/0233988, which are represented by Formula (23) : wherein Ring A and Ring B are one of the followings: (1) Ring A is optionally substituted unsaturated heteromono- cyclic, and Ring B is optionally substituted unsaturated heteromonocyclic, optionally substituted unsaturated fused heterobicyclic, or optionally substituted benzene, (2) Ring A is optionally substituted benzene, and Ring B is optionally substituted unsaturated heteromonocyclic, or optionally substituted unsaturated fused heterobicyclic wherein Y is linked to the heterocyclic ring of said fused heterobicyclic, or (3) Ring A is optionally substituted unsaturated fused heterobicyclic, wherein the sugar moiety X- (sugar) and the moiety -Y- (Ring B) are both on the same heterocyclic ring of said fused heterobicyclic, and Ring B is optionally substituted unsaturated heteromonocyclic, optionally substituted unsaturated fused heterobicyclic, or optionally substituted benzene;
X is carbon or nitrogen; and
Y is - (CH2) n- (wherein n is 1 or 2) ; a pharmaceutically acceptable salt thereof, or a prodrug thereof .
In a preferable embodiment, the SGLT inhibitors are the compounds of Formula (24) :
(24 ) wherein RA is a halogen atom, or a lower alkyl group,- Ring C is a phenyl group substituted by 1-3 substituents selected from the group consisting of a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group, a methylenedioxy group, an ethyleneoxy group, a mono- or di- lower alkylamino group, a carbamoyl group, and a mono- or di-lower alkylcarbamoyl group,- or a heterocyclyl group substituted by 1-3 substituents selected from the group consisting of a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group, a mono- or di-lower alkylamino group, a carbamoyl group, and a mono- or di-lower alkyl- carbamoyl group,- or a pharmaceutically acceptable salt thereof, or a prodrug thereof .
Examples of the preferable compounds include:
1- (β-D-glucopyranosyl) -4-chloro-3- [5- (5-thiazolyl) -2- thienylmethyl] benzene ,-
1- (β-D-glucopyranosyl) -4-chloro-3- (5-phenyl-2-thienyl- methyl) benzene ;
1- (β-D-glucopyranosyl) -4-chloro-3- [5- (2-pyrimidinyl) -2- thienylmethyl] benzene,- 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (2-pyrimidinyl) -2- thienylmethyl] benzene ,-
1- (β-D-glucopyranosyl) -4-chloro-3- [5- (3 -cyanophenyl) -2- thienylmethyl] benzene ,-
1- (β-D-glucopyranosyl) -4-chloro-3- [5- (4 -cyanophenyl) -2- thienylraethyl] benzene;
1- (β-D-glucopyranosyl) -4-chloro-3- [5- (6-fluoro-2-pyridyl) - 2-thienylmethyl] benzene,-
1- (β-D-glucopyranosyl) -4-chloro-3- [5- (6-fluoro-3-pyridyl) - 2-thienylmethyl] benzene,-
1- (β-D-glucopyranosyl) -4-methyl-3- [5- (6-fluoro-2-pyridyl) - 2-thienylmethyl] benzene ; and
1- (β-D-glucopyranosyl) -4-methyl-3- [5- (3-difluoromethyl- phenyl) -2-thienylmethyl] benzene . In an embodiment of the present invention, the SGLT inhibitors are the indole derivatives disclosed in WO 2006/080577 pamphlet, which are represented by Formula (25) :
(25) wherein R1 is halogen, or alkyl, R2 is hydrogen, or halogen, and Ar is one of the following groups
and ΛX in which R3 and R4 are independently hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, hydroxy, phenyl, halophenyl, cyanophenyl, pyridyl, halo- pyridyl, thienyl, or halothienyl, or R3 and R4 together with carbon atoms to which they are attached form a fused benzene, furan or dihydrofuran ring,- or a pharmaceutically acceptable salt thereof.
Examples of the preferable compounds include: 4-chloro-3- (4-ethylphenylmethyl) -1- (β-D-glucopyranosyl) - indole ;
4-chloro-3- (4-ethoxyphenylmethyl) -1- (β-D-glucopyranosyl) - indole ;
3- (5-bromothiophen-2-ylτnethyl) -4-chloro-l- (β-D-gluco- pyranosy1) indo1e ;
3- (4-ethylphenylτnetliyl) -4-fluoro-l- (β-D-glucopyranosyl) - indole ; and
4 -methyl-3- (4-cyclopropylphenylmethyl) -1- (β-D-glucopyranosyl) indole . In an embodiment of the present invention, the SGLT inhibitors are the indole derivatives disclosed in PCT/JP2007/065213, which are represented by Formula (26) :
wherein R1 is fluorine, or chlorine, and R2 is hydrogen, or fluorine, or a pharmaceutically acceptable salt thereof. Examples of the preferable compounds include :
4-chloro-3- (4-cyclopropylphenylmethyl) -1- (β-D-glucopyranosyl) indole ,
3- (4-cyclopropylphenylmethyl) -4-fluoro-l- (β-D-gluco- pyranosy1) indo1e ,
4-chloro-3- (4-cyclopropylphenylmethyl) -6-fluoro-l- (β-D- glucopyranosyl) indole , and
3- (4-cyclopropylphenylmethyl) -4 , 6-difluoro-1- (β-D-glucopyranosyl) indo1e ; and a pharmaceutically acceptable salt thereof.
In an embodiment of the present invention, the SGLT inhibitors are the compounds disclosed in United States Patent Application Publication No. 2004/0259819, which are represented by Formula (27) : wherein
Rl and R2 are each independently F or H or one of said radicals Rl and R2 may be OH; R3 is OH or F, with the proviso that at least one of the radicals Rl, R2 and R3 must be F;
R4 is OH;
A is 0, NH, CH2, S or a bond;
X is C, 0, S or N, with the proviso that X is C when Y is 0 or S;
Y is N, 0 or S; m is 1 or 2 ;
R5 is hydrogen, F, Cl, Br, I, OH, CF3, NO2, CN, COOH, CO(C1- s alkyl) , COO(C1-S alkyl) , CONH2, CONH(C1_6 alkyl) , CON(C1-S alkyl) 2, C^6 alkyl, C2-S alkenyl, C2-6 alkynyl, C1-S alkoxy,
HO-(C1-S alkyl), (C1-S alkyl) -0- (C1-S alkyl), phenyl, benzyl,
Ci-ε alkoxycarbonyl , wherein said CO(C1-S alkyl), COO(C1-S alkyl), CONH(C1-S alkyl), CON(C1-S alkyl)2, C1-S alkyl, C2-6 alkenyl, C2-e alkynyl, C1-S alkoxy, HO-(C1-S alkyl), (C1-S alkyl) -0- (C1-S alkyl) and C1-S alkoxycarbonyl radicals are optionally substituted with one or more fluorine atoms,
SO2-NH2, SO2NH(C1-S alkyl), SO2N(C1-S alkyl) 2, S-(C1-S alkyl),
S- (CH2) o-phenyl, SO- (C1-S alkyl) , SO- (CH2) o-phenyl, SO2-(C1-S alkyl), SO2- (CH2) o-phenyl, wherein said SO2NH(C1-S alkyl), SO2N(C1-S alkyl) 2, S-(C1-S alkyl) , SO- (Ci_6 alkyl) and SO2- (C1-S alkyl) radicals are optionally substituted with one or more fluorine atoms, and wherein the phenyl ring of said S- (CH2) o-phenyl, SO- (CH2) o-phenyl and SO2- (CH2) o-phenyl radicals is optionally mono- or di-substituted with F, Cl, Br, OH, CF3, NO2, CN, OCF3, 0-(C1-S alkyl) , d-6 alkyl or NH2, and wherein o is 0, 1, 2, 3, 4, 5, or 6, NH2, NH-(C1-S alkyl), N(C1-S alkyl) 2, NH(C1-V acyl) , phenyl or 0- (CH2) o-phenyl, wherein the phenyl ring of said phenyl and 0- (CH2) o-phenyl radicals is optionally mono-, di-, or tri-substituted with F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, 0-(C1-S alkyl), C1-S alkyl, NH2, NH(C1-S alkyl), N(C1^5 alkyl) 2, SO2-CH3, COOH, COO-(C1-S alkyl) or CONH2, and wherein o is as hereinabove defined; or, when Y is S, R5 and R6 taken together with the carbon atoms to which they are attached may form a phenyl ring,- R6 is H, Ci-6 alkyl, C1-S alkenyl, C3-s cycloalkyl, or phenyl wherein said phenyl radical is optionally substituted with halogen or C1-^ alkyl;
B is Co-15 alkanediyl, wherein one or more of the carbon atoms in said alkanediyl radical may be replaced, independently of one another, with -0-, -(C=O)-, -CH=CH-, -C≡C-, -S-, -CH(OH)-, -CHF-, -CF2-, -(S=O)-, -(SO2)-, -N(C1-S alkyl)-, -N(C1-S alkyl-phenyl)- or -NH-; n is 0, 1, 2, 3 or 4;
Cycl is a 3-, 4-, 5-, 6- or 7-membered saturated, partially saturated or unsaturated ring, wherein one carbon atom of said ring may be replaced by 0, N or S;
R7, R8 , and R9 are each independently hydrogen, F, Cl, Br, I, OH, CF3, NO2, CN, COOH, COO(C1-S alkyl), CO(Ci_4 alkyl), CONH2, CONH(C1-S alkyl), CON(C1-S alkyl) 2, C1-S alkyl, C2-6 alkenyl, C2.6 alkynyl, C1-S alkoxy, HO-(C1-S alkyl), (C1-S alkyl) -0-(C1-S alkyl) , wherein said COO(C1-S alkyl), CO(Ci_4 alkyl), CONH(C1-S alkyl), CON(C1-S alkyl) 2, C1-S alkyl, C2-S alkenyl, C2-s alkynyl, C1-S alkoxy, HO-(C1-S alkyl) and (C1-S alkyl) -0- (C1- s alkyl) radicals are optionally substituted with one or more fluorine atoms, SO2-NH2, SO2NH(Ci-6 alkyl) , SO2N (Ci_6 alkyl)2, S-(C1-S alkyl) ,
S- (CH2) o-phenyl, SCF3, SO- (C1-S alkyl) , SO- (CH2) o-phenyl, SO2-
(Ci-ε alkyl) , SO2- (CH2) o-phenyl, wherein said SO2NH (Ci-6 alkyl), S02N(Ci-6 alkyl)2, S-(C1-S alkyl) , SO- (C1-S alkyl) and SO2- (C1-S alkyl) radicals are optionally substituted with one or more fluorine atoms, and wherein the phenyl ring of said S- (CH2) o-phenyl, SO- (CH2) o-phenyl and SO2- (CH2) o-phenyl radicals is optionally mono- or di-substituted with F, Cl, Br, OH, CF3, NO2, CN, OCF3, 0-(C1-S alkyl), C1-S alkyl or NH2, and wherein o is as hereinabove defined,
NH2, NH-(C1-S alkyl), N(C1-S alkyl) 2, NH(C1-, acyl) , phenyl or
0- (CH2) o-phenyl, wherein the phenyl ring of said phenyl and 0- (CH2) o-phenyl radicals is optionally mono-, di-, or tri-substituted with F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, C1-S alkoxy, C1-S alkyl, NH2, NH(C1-S alkyl), N(C1-S alkyl) 2, SO2-CH3, COOH, COO-(C1-S alkyl) or CONH2, and wherein o is as hereinabove defined; or R8 and R9 taken together with the carbon atoms to which they are attached form a 5-, 6- or 7-membered, saturated, partially saturated or completely unsaturated ring herein referred to as Cyc2, wherein one or two carbon atom(s) in said Cyc2 ring are optionally replaced by N, 0 or S, and wherein said Cyc2 ring is optionally substituted with C1-S alkyl, C2-5 alkenyl or C2-5 alkynyl, wherein said C1-S alkyl, C2_5 alkenyl and C2_5 alkynyl radicals are optionally substituted with F, Cl, OH, CF3, NO2, CN, C00(C;L-4 alkyl), CONH2, CONH(C1.4 alkyl) or OCF3, and wherein a -CH2- group contained in said C1-S alkyl, C2- 5 alkenyl and C2.5 alkynyl radicals is optionally replaced by -0-; and pharmaceutically acceptable salts thereof.
In an embodiment of the present invention, the SGLT inhibitors are the compounds in United States Patent Application Publication No. 2005/0014704, which are represented by Formula (28) :
wherein: Rl, R2 are each independently OH, F or H with the proviso that when Rl is F, R2 cannot be OH; when Rl is OH, R2 cannot be F; and when Rl is OH, R2 cannot be OH; R3 is OH or F, with the proviso that at least one of said Rl, R2 , R3 radicals must be F,- A is 0, NH, CH2, S or a bond;
R4, R5, and R6 are each independently hydrogen, F, Cl, Br, I, OH, NO2, CN, COOH, CO(C1-S alkyl) , COO(CL6 alkyl) , CONH2, CONH(Ci-S alkyl), CON(C1-S alkyl) 2, Q^6 alkyl, C2-s alkenyl, C2-S alkynyl, Cx-6 alkoxy, HO (Ci.s alkyl), (Cx-6 alkyl) -0- (Ci_6 alkyl), phenyl or benzyl, wherein said CO(C1-S alkyl), COO(C1-S alkyl), CONH (Ci-6 alkyl), CON(C1-S alkyl) 2/ C1-S alkyl, C2-6 alkenyl, C2-s alkynyl, Ci-6 alkoxy, HO(C1-S alkyl), (Ci_6 alkyl) -0- (Ci-e alkyl) radicals are optionally substituted with one or more fluorine atoms,
SO2-NH2, SO2NH(Ci-S alkyl), S02N(d-6 alkyl) 2, S- (Ci-6 alkyl), S- (CH2) o-phenyl, SO- (C1-S alkyl) , SO- (CH2) o-phenyl, SO2-(C1-S alkyl) , SO2- (CH2) o-phenyl , wherein the phenyl ring of said S- (CH2) o-phenyl, SO- (CH2) o-phenyl and SO2- (CH2) o-phenyl radicals may be mono- or disubstituted with F, Cl, Br, OH, CF3, NO2, CN, OCF3, 0-(Cx-S alkyl), C1-S alkyl or NH2 and wherein o is 0, 1, 2, 3, 4, 5 or 6, NH2, NH-(Ci-S alkyl) , N(C1^6 alkyl)2, NH(Ci.7 acyl) , phenyl,
O- (CH2) o-phenyl, wherein the phenyl ring of said phenyl and 0- (CH2) o-phenyl radicals may be mono-, di-, or trisubstituted with F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, 0-(C1-6 alkyl), Ci.6 alkyl,
NH2, NH(Ci-s alkyl), N(Ci-S alkyl)2, SO2-CH3, COOH, COO- (Ci-S alkyl) or CONH2 and wherein o is as hereinabove defined;
B is Co-is alkanediyl, wherein one or more carbon atoms in said C0-I5 alkanediyl radical are, independently of one another, optionally replaced by -0-, -(C=O)-, -CH=CH-, -C≡C-, -S-, -CH(OH)-, -CHF-, -CF2-, -(S=O)-, -(SO2)-, -N(Ci-S alkyl) -, -N(C1-S alkyl-phenyl)- or -NH-; n is 0, 1, 2, 3 or 4,- Cycl is a 3-, 4-, 5-, 6-, or 7-membered saturated, partially saturated or unsaturated ring, wherein one carbon atom of said ring may be replaced by 0, N or S ;
R7, R8, R9 R7, R8 , and R9 are each independently hydrogen,
F, Cl, Br, I, OH, CF3, NO2, CN, COOH, COO(C1-S alkyl), CO(C1- 4 alkyl), CONH2, CONH(C1-S alkyl), CON(C1-S alkyl)2, C1^ alkyl,
C2-s alkenyl, C2.e alkynyl, Ci-8 alkoxy, HO- (Ci-6 alkyl), (C1-S alkyl) -0- (C1-S alkyl) , wherein said COO(C1-S alkyl), CO(C!-4 alkyl), CONH(C1-S alkyl), CON(C1-S alkyl)2, C1-S alkyl, C2-s alkenyl, C2.s alkynyl, C1-S alkoxy, HO-(Cx-S alkyl) and (C1-S alkyl) -0- (Ci- 6 alkyl) radicals are optionally substituted with one or more fluorine atoms,
SO2-NH2, SO2NH(C1-S alkyl), SO2N(C1-S alkyl) 2, S-(C1-S alkyl),
S- (CH2) o-phenyl, SO-(C1-S alkyl), SO- (CH2) o-phenyl, SO2-(C1-S alkyl), SO2- (CH2) o-phenyl, wherein said SO2NH(Ci-S alkyl), SO2N(C1-S alkyl)2, S-(C1-S alkyl) , SO- (Ci-e alkyl) and SO2- (Ci_6 alkyl) radicals are optionally substituted with one or more fluorine atoms, and wherein the phenyl ring of said S- (CH2) o-phenyl, SO- (CH2) o-phenyl and SO2- (CH2) o-phenyl radicals is optionally mono- or disubstituted with F, Cl, Br, OH, CF3, NO2, CN, OCF3, O- (Ci-e alkyl) , Cx-6 alkyl or NH2, and wherein o is as hereinabove defined,
NH2, NH- (Ci-6 alkyl), N(C1-S alkyl) 2/ NH(C1-? acyl) , phenyl or
0- (CH2) o-phenyl, wherein the phenyl ring of said phenyl and 0- (CH2) o-phenyl radicals is optionally mono-, di-, or trisubstituted with F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, Ci-8 alkoxy, Ci-e alkyl, NH2, NH(C1-S alkyl), N(C1-5 alkyl) 2, SO2-CH3, COOH, COO- (C1-S alkyl) or CONH2, and wherein o is as hereinabove defined; or R8 and R9 taken together with the carbon atoms to which they are attached form a 5-, 6- or 7-membered, saturated, partially saturated or unsaturated ring herein referred to as Cyc2, wherein one or two carbon atotn(s) in said Cyc2 ring are optionally replaced by N, 0 or S, and wherein said Cyc2 ring is optionally substituted with
Ci-S alkyl, C2-s alkenyl or C2-s alkynyl, wherein said Ci_s alkyl, C2.5 alkenyl and C2-s alkynyl radicals are optionally substituted with F, Cl, OH, CF3, NO2, CN, COO(CL4 alkyl), CONH2, CONH (Ci-4 alkyl) or OCF3, and wherein a -CH2- group contained in said Ci_6 alkyl, C2- 5 alkenyl and C2-5 alkynyl radicals is optionally replaced by -0-; and pharmaceutically acceptable salts thereof.
DPP4 inhibitors are well known to those skilled in the art, and examples of DPP4 inhibitors can be found in the following publications: (1) TANABE SEIYAKU Co., Ltd.: WO 02/30891 or the corresponding U.S. patent (No. 6,849,622); and WO 02/30890 or the corresponding U.S. patent (No. 7,138,397); .
(2) Ferring BV: WO 95/15309, WO 01/40180, WO 01/81304, WO
01/81337, WO 03/000250, and WO 03/035057; (3) Probiodrug: WO 97/40832, EP1082314, WO 99/61431, WO
03/015775; (4) Novartis AG: WO 98/19998, WO 00/34241, WO 01/96295, US 6,107,317, US 6,110,949, and US 6,172,081;
(5) GlaxoSmithKline: WO 03/002531, WO 03/002530, and WO 03/002553; (6) Bristol Myers Squibb: WO 01/68603, WO 02/83128, and WO 2005/012249;
(7) Merck & Co.: WO 02/76450, and WO 03/004498;
(8) Srryx Inc.: WO 2005/026148, WO 2005/030751, WO 2005/095381, WO 2004/087053, and WO 2004/103993; (9) Mitsubishi Pharma Corp.: WO 02/14271, US 7,060,722, US
7,074,794, WO 2003/24942, Japan Patent Publication No.
2002-265439, Japan Patent Publication No. 2005-170792, and
WO 2006/088129;
(10) Taisho Pharma Co., Ltd.: WO 2004/020407; (12) Yamanouchi Pharmaceutical Co., Ltd.: WO 2004/009544,-
(13) Kyowa Hakko Kogyo : WO 02/051836;
(14) Kyorin Seiyaku: WO 2005/075421, WO 2005/077900, and WO 2005/082847;
(15) Alantos Pharmaceuticals: WO 2006/116157; (16) Glenmark Pharmaceuticals: WO 2006/090244, and WO 2005/075426;
(17) Sanwa Kagaku Kenkyusho : WO 2004/067509; and
(18) LG lifescience: WO 2005/037828, and WO 2006/104356.
In a preferable embodiment of the present invention, DPP4 inhibitors are the aliphatic nitrogen-containing 5- membered ring compounds disclosed in US 6,849,622, which are represented by Formula (29) :
wherein A represents -CH2- or -S-, R1 represents hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group or a lower alkoxy lower alkyl group, and R2 represents (1) a cyclic group which may be substituted, where the cyclic group portion is (i) a monocyclic, bicyclic or tricyclic hydrocarbon group, or (ii) a monocyclic, bicyclic or tricyclic heterocyclic group, or (2) an amino group which may be substituted, or a pharmaceutically acceptable salt thereof .
Examples of the preferable compounds include:
(2S) -2-cyano-l- [trans-4- (dimethylaminocarbonyl) cyclohexyl- amino] acetylpyrrolidine; (2S) -2-cyano-l- [trans-4- (morpholinocarbonyl) cyclohexyl- amino] acetylpyrrolidine; and
(2S) -2-cyano-l- [trans-4- (4-acetylpiperazin-l-ylcarbonyl) - eyelohexylamino] acetylpyrrolidine ; and a pharmaceutically acceptable salt (e.g., besylate) of the above compounds .
In another preferable embodiment, DPP4 inhibitors are the aliphatic nitrogen-containing 5-membered ring compounds disclosed in US 7,138,397, which are represented by Formula (30) :
wherein A is -CH2-, R1 is H, a lower alkyl group, a hydroxy lower alkyl group or a lower alkoxy lower alkyl group, and
R2 is a piperazinyl group which may be substituted, or a pharmaceutically acceptable salt thereof.
Examples of the preferable compounds include:
(S) -2-cyano-l- [t-4- (4-acetyl-l-piperazinyl) -1-methyl-r-1- eyelohexylamino] acetylpyrrolidine; and
(S) -2-cyano-l- [t-4- (4 -propionyl-1-piperazinyl) -1-methyl-r- 1-eyelohexylamino] acetylpyrrolidine; or a pharmaceutically acceptable salt thereof. In another preferable embodiment, DPP4 inhibitors are the compounds disclosed in US 7,074,794, which are represented by Formula (31) :
wherein:
X is -NR1R2 wherein R1 and R2 may be the same or different and each is independently cycloalkylalkyl, arylalkyl, heteroaryl or heteroarylalkyl , or may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents, and the heterocycle optionally being a spiro ring, -NR3COR4 wherein R3 and R4 are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl or heteroarylalkyl,
-NR5CONR5R7 or -NR5CH2CH2NR5R7 wherein R5, Rs and R7 are the same or different and each is independently hydrogen atom, alkyl, acyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or Re and R7 may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents,
-NR8SO2R9 wherein R8 and R9 are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl , or -OR10 or -OCOR11 wherein R10 and R11 are each a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, Y is CH2/ CH-OH, S, S=O or SO2, Z is a hydrogen atom or cyano, and of the above-mentioned groups, alkyl, aryl, arylalkyl, arylalkenyl , heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl and heterocycle each optionally have substituents , or a pharmaceutically acceptable salt thereof.
In this embodiment, a more preferable compound is 3- [ (2S, 4S) -4- [4- (3 -methyl-1-phenyl-lH-pyrazol-5 -yl)piperazin- 1-yl] pyrrolidin-2-yl] thiazolidine or a pharmaceutically acceptable salt thereof (e.g., hydrobromide) .
In another preferable embodiment of the present invention, the DPP4 inhibitor is Sitagliptin [developing code: MK- 0431; proprietary name: Januvia; chemical name: (3R) -3 -amino-1- [9- (trifluoromethyl) -1,4,7, 8-tetraza- bicyclo [4.3.0] nona-6 , 8-dien-4-yl] -4- (2,4, 5-trifluoro- phenyl) butan-1-one] , or an equivalent thereof such as a pharmaceutically acceptable salt thereof (e.g., phosphate).
In another preferable embodiment of the present invention, the DPP4 inhibitor is Vildagliptin [developing code: LAF237; proprietary name: Galvus ; chemical name: (2S) -1- [2- [ (3 -hydroxy-1-adamantyl) amino] acetyl] pyrrolidine- 2-carbonitrile] , or an equivalent thereof such as a pharmaceutically acceptable salt thereof .
In still another preferable embodiment of the present invention, the DPP4 inhibitor is Saxagliptin (developing code: BMS-477118; chemical name : (IS73S, 5S) -2- [ (2S) -2- amino-2- (3 -hydroxy-1-adamantyl) acetyl] -2-azabicyclo [3.1.0]- hexane-3-carbonitrile) , or an equivalent thereof such as a pharmaceutically acceptable salt thereof.
In still another preferable embodiment of the present invention, the DPP4 inhibitor is Alogliptin (developing code: SYR-322; chemical name: 6- [ (3R) -3-aminopiperidin-l- yl] -1- (2-cyanobenzyl) -3-methylpyrimidin-2, 4 (IH, 3H) -dione) , or an equivalent thereof such as a pharmaceutically acceptable salt thereof (e.g., benzoate) .
In an embodiment of the present invention, the DPP4 inhibitor is L-threo-isoleucyl pyrrolidide, L-allo-iso- leucyl thiazolidide, or L-allo-isoleucyl pyrrolidide, or a pharmaceutically acceptable salt thereof.
As mentioned above, the present invention relates to a method for treating or preventing a disease which is associated with plasma active GLP-I level comprising administering to a patient in need thereof a therapeutically effective amount of an SGLT inhibitor and a DPP4 inhibitor in combination.
In an embodiment of the present invention, the SGLT inhibitor and the DPP4 inhibitor are administered in amounts sufficient to lower a blood glucose level in the patient.
In another aspect, the present invention relates to a method for increasing plasma active GLP-I level comprising administering to a patient a therapeutically effective amount of an SGLT inhibitor and a DPP4 inhibitor in combination.
In an embodiment of the present invention, the SGLT inhibitor and the DPP4 inhibitor are administered in amounts sufficient to increase plasma active GLP-I level in the patient .
A combination therapy of the present invention is useful in treating or preventing a disease which is associated with plasma active GLP-I level in a mammal such as a human.
In another aspect, the present invention relates to a pharmaceutical composition comprising an SGLT inhibitor, a DPP4 inhibitor and a pharmaceutically acceptable carrier or diluent.
In an embodiment of the present invention, the pharmaceutical composition of the present invention can be used as an agent to lower a blood glucose level in a patient .
In an embodiment of the present invention, the pharmaceutical composition of the present invention can be used as an agent to increase plasma active GLP-I level in a patient .
In an embodiment of the present invention, the pharmaceutical composition of the present invention can be used as an agent for treatment or prevention of a disease which is associated with plasma active GLP-I level.
Examples of a disease which is associated with plasma active GLP-I level include diabetes, a condition related to diabetes, obesity, myocardial infarction, stroke, learning or memory impairment, and a neurodegenerative disorder. Examples of a condition related to diabetes include hyperglycemia, impaired glucose tolerance, impaired fasting glucose, insulin resistance, pancreatic β-cell insufficiency, enteroendocrine cell insufficiency, glucosuria, metabolic acidosis, cataracts, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic coronary artery disease, diabetic cerebrovascular disease, diabetic peripheral vascular disease, metabolic syndrome, hyperlipidemia, atherosclerosis, hypertension, and obesity. Examples of a neurodegenerative disorder include excito- toxic brain damage caused by severe epileptic seizures, Alzheimer's disease, Parkinson's disease, Huntington's disease, prion-associated disease, motor-neuron disease, traumatic brain injury, spinal cord injury, and peripheral neuropathy. Diabetes includes Type 1 or Type 2 diabetes.
The SGLT inhibitors and the DPP4 inhibitors may be administered to a patient by any conventional route of administration, including intravenous, oral, subcutaneous, intramuscular, intradermal and parenteral administration. The SGLT inhibitors and the DPP4 inhibitors can be administered simultaneously, sequentially, or at separate intervals. When simultaneously administered, the SGLT inhibitor and the DPP4 inhibitor can be incorporated into a single pharmaceutical composition or into separate compositions. When separately administered, therapeutically effective amounts of the SGLT inhibitor and the DPP4 inhibitor can be administered on a different schedule. Each composition may be formulated with common excipients, diluents or carriers, and compressed into tablets, or formulated elixirs or solutions; and as sustained relief dosage forms and the like . The SGLT inhibitor and the DPP4 inhibitor may be administered via different routes.
The SGLT inhibitor and the DPP4 inhibitor are provided in amounts to give a synergistic effect in increasing plasma active GLP-I level in a patient. Optimal dose of the SGLT inhibitor and the DPP4 inhibitor will vary with patient's age, weight, sex, the particular compound used, the route of administration, and severity of the condition.
In another aspect, the present invention relates to a pharmaceutical composition comprising an SGLT inhibitor and DPP4 inhibitor, together with at least one pharmaceutically acceptable carrier or excipient. In another aspect, the present invention relates to the use of an SGLT inhibitor and a DPP4 inhibitor for the manufacture of a medicament for the treatment or prevention of a disease associated with plasma active GLP-I level.
In another aspect, the present invention relates to the use of an SGLT inhibitor and a DPP4 inhibitor for the manufacture of a medicament for the treatment or prevention of diabetes .
In another aspect, the present invention relates to a product comprising an SGLT inhibitor and DPP4 inhibitor as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of a disease associated with plasma active GLP-I level.
In another aspect, the present invention relates to a product comprising a SGLT inhibitor and a DPP4 inhibitor as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of diabetes.
The pharmaceutical composition of the present invention is preferably in unit dosage forms such as tablets, capsules, powders, granules, solutions, suspen- sions, syrups, aerosol, and suppositories.
The pharmaceutical composition can be formulated with suitable pharmaceutically acceptable carriers and diluents. Suitable pharmaceutically acceptable carriers and diluents are available to those skilled in the art [see, e.g.,
Remington: The Science and Practice of Pharmacy, (Gennaro et al., eds . ) , 20th Edition, 2000]. Examples of the suitable carriers and diluents can include stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, magnesium carbonate, talc, gelatin, tragacanth, dextran sulfate sodium, sodium carboxymethylcellulose, methylcellulose, sodium alginate, pectin, dextrin, mannitol, sorbitol, lactose, sucrose, starch, cocoa butter, polyvinyl-pyrrolidone, polyvinyl alcohol, polyethylene glycols, propylene glycol, ethanol, corn oil, cottonseed oil, coconut oil, peanut oil, sesame oil, benzyl alcohol, and other pharmaceutically acceptable materials.
Pharmaceutical compositions may be prepared by methods well known to those skilled in the art, e.g., by means of conventional mixing, dissolving, granulation, levigation, emulsifying, encapsulation, entrapping, lyophilization or spray drying.
In a preferable embodiment of the present invention, the SGLT inhibitor is a compound of Formula (23) or a pharmaceutically acceptable salt thereof, described above.
In another preferable embodiment of the present invention, the SGLT inhibitor is a compound of Formula (24) or a pharmaceutically acceptable salt thereof, described above .
In another preferable embodiment of the present invention, the SGLT inhibitor is a compound of Formula (25) or a pharmaceutically acceptable salt thereof, described above .
In another preferable embodiment of the present invention, the SGLT inhibitor is a compound of Formula (26) or a pharmaceutically acceptable salt thereof, described above . In a more preferable embodiment of the present invention, the SGLT inhibitor is Sergliflozin, Remogliflozin or Dapagliflozin, or a pharmaceutically acceptable salt thereof .
In a preferable embodiment of the present invention, the DPP4 inhibitor is a compound of Formula (29) or a pharmaceutically acceptable salt thereof, described above.
In another preferable embodiment of the present invention, the DPP4 inhibitor is a compound of Formula (30) or a pharmaceutically acceptable salt thereof, described above .
In another preferable embodiment of the present invention, the DPP4 inhibitor is a compound of Formula (31) or a pharmaceutically acceptable salt thereof, described above .
In another preferable embodiment of the present invention, the DPP4 inhibitor is Sitagliptin, Vildagliptin, Saxagliptin or Alogliptin, or a pharmaceutically acceptable salt thereof.
In a more preferable embodiment of the invention, the SGLT inhibitor is Sergliflozin, Remogliflozin or Dapagliflozin, or a pharmaceutically acceptable salt thereof, and the DPP4 inhibitor is Sitagliptin, Vildagliptin, Saxagliptin or Alogliptin, or a pharmaceutically acceptable salt thereof.
Preferable examples of combination of the SGLT inhibitor and DPP4 inhibitor of the present invention include the following:
(a) The SGLT inhibitor is a compound of Formula (23) :
wherein Ring A and Ring B are one of the followings : (1) Ring A is optionally substituted unsaturated heteromono- cyclic, and Ring B is optionally substituted unsaturated heteromonocyclic, optionally substituted unsaturated fused heterobicyclic, or optionally substituted benzene, (2) Ring A is optionally substituted benzene, and Ring B is optionally substituted unsaturated heteromonocyclic, or optionally substituted unsaturated fused heterobicyclic wherein Y is linked to the heterocyclic ring of said fused heterobicyclic, or (3) Ring A is optionally substituted unsaturated fused heterobicyclic, wherein the sugar moiety X- (sugar) and the moiety -Y- (Ring B) are both on the same heterocyclic ring of said fused heterobicyclic, and Ring B is optionally substituted unsaturated heteromonocyclic, optionally substituted unsaturated fused heterobicyclic, or optionally substituted benzene; X is carbon or nitrogen; and
Y is - (CH2) n- (wherein n is 1 or 2); or a pharmaceutically acceptable salt thereof, and the DPP4 inhibitor is a compound of formula (29) :
wherein A represents -CH2- or -S-, R1 represents hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group or a lower alkoxy lower alkyl group, and R2 represents (1) a cyclic group which may be substituted, where the cyclic group portion is (i) a monocyclic, bicyclic or tricyclic hydrocarbon group, or (ii) a monocyclic, bicyclic or tricyclic heterocyclic group, or (2) an amino group which may be substituted, or pharmaceutically acceptable slat thereof ; or the DPP4 inhibitor is a compound of Formula (31) : wherein :
X is -NR1R2 wherein R1 and R2 may be the same or different and each is independently cycloalkylalkyl, arylalkyl, heteroaryl or heteroarylalkyl, or may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents, and the heterocycle optionally being a spiro ring,
-NR3COR4 wherein R3 and R4 are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl or heteroarylalkyl, -NR5CONR6R7 or -NR5CH2CH2NR6R7 wherein R5, R6 and R7 are the same or different and each is independently hydrogen atom, alkyl, acyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or R6 and R7 may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents,
-NR8SO2R9 wherein R8 and R9 are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or
-OR10 or -OCOR11 wherein R10 and R11 are each a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl,' arylalkyl, heteroaryl or heteroarylalkyl, Y is CH2, CH-OH, S, S=O or SO2,
Z is a hydrogen atom or cyano, and of the above-mentioned groups, alkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl and heterocycle each optionally have substituents, or a pharmaceutically acceptable salt thereof; or the DPP4 inhibitor is Sitagliptin or a pharmaceutically acceptable salt thereof;
(b) The SGLT inhibitor is a compound of Formula (24)
(24) wherein RA is a halogen atom, or a lower alkyl group; Ring C is a phenyl group substituted by 1-3 substituents selected from the group consisting of a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group, a methyl- enedioxy group, an ethyleneoxy group, a mono- or di-lower alkylamino group, a carbamoyl group, and a mono- or di- lower alkylcarbamoyl group; or a heterocyclyl group substituted by 1-3 substituents selected from the group consisting of a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a halo- lower alkoxy group, a mono- or di-lower alkylamino group, a carbamoyl group, and a mono- or di-lower alkylcarbamoyl group ; or a pharmaceutically acceptable salt thereof, or a prodrug thereof, and the DPP4 inhibitor is a compound of formula (29) : wherein A represents -CH2- or -S-, R1 represents hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group or a lower alkoxy lower alkyl group, and R2 represents (1) a cyclic group which may be substituted, where the cyclic group portion is (i) a monocyclic, bicyclic or tricyclic hydrocarbon group, or (ii) a monocyclic, bicyclic or tricyclic heterocyclic group, or (2) an amino group which may be substituted, or a pharmaceutically acceptable slat thereof; or the DPP4 inhibitor is a compound of Formula (31) :
wherein: X is -NR1R2 wherein R1 and R2 may be the same or different and each is independently cycloalkylalkyl, arylalkyl, heteroaryl or heteroarylalkyl, or may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents, and the heterocycle optionally being a spiro ring,
-NR3COR4 wherein R3 and R4 are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl or heteroarylalkyl,
-NR5CONR5R7 or -NR5CH2CH2NR5R7 wherein R5, R6 and R7 are the same or different and each is independently hydrogen atom, alkyl, acyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or Rs and R7 may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents ,
-NR8SO2R9 wherein R8 and R9 are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl , arylalkyl, heteroaryl or heteroarylalkyl , or -OR10 or -OCOR11 wherein R10 and R11 are each a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, Y is CH2, CH-OH, S, S=O or SO2, Z is a hydrogen atom or cyano, and of the above-mentioned groups, alkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl and heterocycle each optionally have substituents, or a pharmaceutically acceptable salt thereof; or the DPP4 inhibitor is Sitagliptin or a pharmaceutically acceptable salt thereof;
(c) the SGLT inhibitor is a compound of Formula (26) :
wherein R1 is fluorine, or chlorine, and R2 is hydrogen, or fluorine, or a pharmaceutically acceptable salt thereof; and the DPP4 inhibitor is a compound of formula (29) : wherein A represents -CH2- or -S-, R1 represents hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group or a lower alkoxy lower alkyl group, and R2 represents (1) a cyclic group which may be substituted, where the cyclic group portion is (i) a monocyclic, bicyclic or tricyclic hydrocarbon group, or (ii) a monocyclic, bicyclic or tricyclic heterocyclic group, or (2) an amino group which may be substituted, or a pharmaceutically acceptable slat thereof; or the DPP4 inhibitor is a compound of Formula (31) :
wherein: X is -NR1R2 wherein R1 and R2 may be the same or different and each is independently cycloalkylalkyl, arylalkyl, heteroaryl or heteroarylalkyl, or may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents, and the heterocycle optionally being a spiro ring,
-NR3COR4 wherein R3 and R4 are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl or heteroarylalkyl,
-NR5CONR6R7 or -NR5CH2CH2NR5R7 wherein R5, R6 and R7 are the same or different and each is independently hydrogen atom, alkyl, acyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or R6 and R7 may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents,
-NR8SO2R9 wherein R8 and R9 are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl , or -OR10 or -OCOR11 wherein R10 and R11 are each a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, Y is CH2, CH-OH, S, S=O or SO2, Z is a hydrogen atom or cyano, and of the above-mentioned groups, alkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl and heterocycle each optionally have substituents, or a pharmaceutically acceptable salt thereof; or the DPP4 inhibitor is Sitagliptin or a pharmaceutically acceptable salt thereof; and
(d) the SGLT inhibitor is selected from:
(i) 1- (β-D-Glucopyranosyl) -4-chloro-3- [5- (6-fluoro-2- pyridyl) -2-thienylmethyl] benzene or a pharmaceutically acceptable salt thereof;
(ii) 3- (5- (4 -Fluorophenyl) -2 -thienylmethyl) -1- (β-D-gluco- pyranosyl) -4-methylbenzene or a pharmaceutically acceptable salt thereof;
(iii) 1- (β-D-Glucopyranosyl) -4-chloro-3- [5- (6-fluoro-3- pyridyl) -2 -thienylmethyl] benzene or a pharmaceutically acceptable salt thereof;
(iv) 3- (4-Cyclopropylphenylmethyl) -4-fluoro-l- (β-D-gluco- pyranosyl) indole or a pharmaceutically acceptable salt thereof ; and (v) 3- (4-Cyclopropylphenylmethyl) -4, 6-difluoro-1- (β-D- glucopyranosyl) indole or a pharmaceutically acceptable salt thereof ; and the DPP4 inhibitor is selected from:
(i) 3- [ (2S,4S) -4- [4- (3 -methyl-1-phenyl-lH-pyrazol-5-yl) - piperazin-1-yl] pyrrolidin-2-ylcarbonyl] thiazolidine or a pharmaceutically acceptable salt thereof (e.g., hydro- bromide) ;
(ii) Sitagliptin (i.e., (3R) -3-amino-l- [3- (trifluoro- methyl) -5,6,7, 8-tetrahydro-5H- [1,2,4] triazolo [4, 3-a]pyra- zin-7-yl] -4- (2,4, 5-trifluorophenyl) butan-1-one) or a pharmaceutically acceptable salt thereof (e.g., phosphate); and
(iii) (2S) -2-cyano-l- [trans-4- (dimethylaminocarbonyl) - cyclohexylamino] acetylpyrrolidine or a pharmaceutically acceptable salt thereof (e.g., besylate) .
When the SGLT inhibitor is to be administered orally or parenterally, the dose can typically be selected from a range of about 0.01 to 100 mg/kg/day, preferably about 0.01 to 30 mg/kg/day. When the SGLT inhibitor is to be administered orally, the dose can typically be selected from a range of about 0.03 to 100 mg/kg/day, preferably about 0.03 to 30 mg/kg/day, more preferably about 0.03 to 10 mg/kg/day. When the SGLT inhibitor is to be administered parenterally, the dose can typically be selected from a range of about 0.01 to 30 mg/kg/day, preferably about 0.01 to 10 mg/kg/day, more preferably about 0.01 to 3 mg/kg/day.
When the DPP4 inhibitor is to be administered orally or parenterally, the dose can typically be selected from a range of about 0.01 to 30 mg/kg/day, preferably about 0.01 to 10 mg/kg/day. When the DPP4 inhibitor is to be administered orally, the dose can typically be selected from a range of about 0.03 to 30 mg/kg/day, preferably about 0.03 to 10 mg/kg/day, more preferably about 0.03 to 3 mg/kg/day. When the DPP4 inhibitor is to be administered parenterally, the dose can typically be selected from a range of about 0.01 to 10 tng/kg/day, preferably about 0.01 to 3 mg/kg/day, more preferably about 0.01 to 1 mg/kg/day.
The dose ratio between the respective inhibitors can be selected appropriately, based on patient's age, weight, sex, severity of conditions, and route of administration. For example, the weight : weight dose ratio between the DPP4 inhibitor and the SGLT inhibitor (DPP4 inhibitor : SGLT inhibitor) may typically fall within a range of 1:0.01 to 1:600, preferably 1:0.1 to 1:300, more preferably 1:0.5 to 1:30.
According to the present invention, both the SGLT inhibitor and the DPP4 inhibitor can be administered once or several times at the daily dose described above.
EXAMPLES
Example 1:
Effects of the SGLT inhibitor on plasma active GLP-I level in glucose-loaded DPP4 -deficient rats
(a) Animals: DPP4-deficient male Fisher rats (purchased from Charles River Japan, Inc.)
(b) Methods:
(b-1) Preparation and Administration of Test Compound The test compound was suspended in a solution of 0.5% carboxymethyl cellulose containing 0.2% Tween 80 at the doses indicated in Table 1, and administered to the test group orally at a volume of 5 mL/kg. The vehicle control group was orally administered a solution of 0.5% carboxy- methyl cellulose containing 0.2% Tween 80 at a volume of 5 mL/kg. Just after the administration of the compound or vehicle, a glucose solution (2 g/kg/5 ml) was given orally.
(b-2) Procedure of Blood Collection and Determination of Plasma Active GLP-I Level
Blood was collected from the caudal vein of an unanesthetized rat just before and 0.5, 1, and 3 hours after glucose loading. Plasma active GLP-I level was determined by using RAT ENDOCRINE LINCOpIex KIT (LINCO Research) .
(b-3) Test Compound
The following compound was used: Compound A:
1- (β-D-glucopyranosyl) -4-chloro-3- [5- (6-fluoro-2- pyridyl) -2-thienylmethyl] benzene (see: United States Patent Application Publication No. 2005/0233988) .
(c) Results:
The results are shown in Table 1
Table 1
The results are expressed as means + SEM (n=6) . Statistical differences between groups were assessed by
Dunnett ' s method. * ; P<Cθ.O5, **; P<0.01 vs. control group,
As shown in the above table 1, Compound A markedly increased, plasma active GLP-I level in DPP4-deficient rats. This result suggests that the augmentation of plasma active GLP-I by compound A is DPP4 - independent . The most likely- explanation for the finding in that Compound A increases the secretion of GLP-I.
Example 2 :
Synergistic effect of the SGLT inhibitor and the DPP4 inhibitor on plasma active GLP-I level in glucose-loaded normal rats
(a) Animals:
DPP4 -positive male Fisher rats (purchased from Japan SLC, Inc. )
(b) Methods :
(b-1) Preparation and Administration of Test Compounds
Each test compound was suspended in a solution of 0.5% carboxymethyl cellulose containing 0.2% Tween 80 at the doses indicated in Table 2, and administered to the test group orally at a volume of 5 mL/kg. The vehicle control group was orally administered a solution of 0.5% carboxymethyl cellulose containing 0.2% Tween 80 at a volume of 5 mL/kg. Just after the administration of the compound or vehicle, a glucose solution (2 g/kg/5 mL) was given orally.
(b-2) Procedure of Blood Collection and Determination of Plasma Active GLP-I Level Blood was collected from the caudal vein of an unanesthetized rat just before and 0.2, 0.5, 1, and 2 hours after glucose loading. Plasma active GLP-I level was determined by using RAT ENDOCRINE LINCOplex KIT (LINCO Research) .
(b-3) Test Compounds The following compounds were used: Compound A:
1- (β-D-Glucopyranosyl) -4-chloro-3- [5- (6-fluoro-2- pyridyl) -2 -thienylmethyl] benzene,- and Compound B:
(2S) -2-Cyano-l- [trans-4- (morpholinocarbonyl) cyclo- hexylamino] acetylpyrrolidine (see: United States Patent No. 6, 849, 622) .
(c) Results:
The results are shown in Table 2 :
Table 2
The results are expressed as means + SEM (n=6) . Statistical differences between groups were assessed by
Dunnett's method. * ; P<0.05, **; P<Cθ.Ol vs. control group.
As shown in Table 2 , when the SGLT inhibitor was given separately, there was no increase in the active GLP-I levels . The DPP4 inhibitor treatment alone increased in plasma active GLP-I only at 0.2 hr. On the other hand, the combination treatment of Compound A and Compound B produced marked and prolonged increase of plasma active GLP-I level in DPP4 -positive rats.
Example 3 :
Effects of the SGLT inhibitor and the DPP4 inhibitor on plasma active GLP-I level in glucose-loaded diabetic mice.
(a) Animals:
Male BKS-Cg-+ mice,- an Animal Model of Type 2 Diabetes (Purchased from CLEA Japan, Inc.)
(b) Methods: (b-1) Preparation and Administration of Test Compounds Each test compound was suspended in a solution of
0.5% carboxymethyl cellulose containing 0.2% Tween 80 at the doses indicated in Table 3 , and administered to the test group orally at a volume of 5 mL/kg. The vehicle control group was orally administered a solution of 0.5% carboxymethyl cellulose containing 0.2% Tween 80 at a volume of 5 mL/kg. Just after the administration of the compound or vehicle, a glucose solution (2 g/kg/5 mL) was given orally.
(b-2) Procedure of Blood Collection and Determination of
Plasma Active GLP-I Level
Blood was collected from the caudal vein of an unanesthetized mice just before and 0.5, 1, and 2 hours after glucose loading. Plasma active GLP-I level was determined by using RAT ENDOCRINE LINCOplex KIT (LINCO
Research) .
(b-3) Test Compounds The following compounds were used: Compound A: 1- (β-D-Glucopyranosyl) -4-chloro-3- [5- (6-fluoro-2- pyridyl) -2 -thienylmethyl] benzene,- and Compound B :
(2S) -2-Cyano-l- [trans-4- (morpholinocarbonyl) cyclo- hexylamino] acetylpyrrolidine .
(c) Results:
The results are shown in Table 3.
Table 3
The results are expressed as means + SEM (n=8) . Statistical differences between groups were assessed by Dunnett ' s method. * ; P<Cθ.O5, **; P<0.01 vs. control group,
As shown in table 3 , not only in normal animal but also in animal model of Type 2 diabetes, the combination of Compound A and Compound B significantly increased plasma active GLP-I level.
Example 4 :
Synergistic effect of the SGLT inhibitor and the DPP4 inhibitor on plasma active GLP-I level in glucose-loaded normal rats (a) Animals :
DPP4 -positive male Fisher rats (purchased from Japan SLC, Inc.)
(b) Methods:
(b-1) Preparation and Administration of Test Compounds
Each test compound was suspended in a solution of 0.5% carboxymethyl cellulose containing 0.2% Tween 80 at the doses indicated in Table 4, 5 or 6, and administered to the test group orally at a volume of 5 mL/kg. The vehicle control group was orally administered a solution of 0.5% carboxymethyl cellulose containing 0.2% Tween 80 at a volume of 5 mL/kg. Just after the administration of the compound or vehicle, a glucose solution (2 g/kg/5 mL) was given orally.
(b-2) Procedure of Blood Collection and Determination of Plasma Active GLP-I Level
Blood was collected from the caudal vein of an unanesthetized rat at appropriate time described in the table. Piasma active GLP-I level was determined by using RAT ENDOCRINE LINCOplex KIT (LINCO Research) .
(b-3) Test Compounds The following compounds were used for the tests: Compound C:
3- (5- (4 -Fluorophenyl) -2-thienylmethyl) -1- (β-D-gluco- pyranosyl) -4-methylbenzene (see: United States Patent Application Publication No. 2005/0233988); Compound D:
1- (β-D-Glucopyranosyl) -4-chloro-3- [5- (6-fluoro-3- pyridyl) -2-thienylmethyl] benzene (see: United States Patent Application Publication No. 2005/0233988) ; Compound E : 3- (4-Cyclopropylphenylmethyl) -4-fluoro-l- (β-D-gluco- pyranosyl) indole (see: WO 2008/013322 pamphlet); Compound F:
3- (4-Cyclopropylphenylmethyl) -4, 6-dif luoro-1- (β-D- glucopyranosyl) indole (see: WO 2008/013322 pamphlet) ; Compound G :
3- [ (2S,4S) -4- [4- (3-methyl-l-phenyl-lH-pyrazol-5- yl)piperazin-l-yl] pyrrolidin-2-ylcarbonyl] thiazolidine hydrobromide (see United States Patent No. 7,074,794) ; Compound H :
Sitagliptin phosphate; and Compound I:
(2S) -2-cyano-l- [trans-4- (dimethylaminocarbonyl) cyclo- hexylamino] acetylpyrrolidine besylate (see : United States Patent No. 6,849,622) .
(c) Results:
The results are shown in Tables 4-6
Table 4
The results are expressed as means ± SEM (n = 5 or 6) . Statistical differences between groups were assessed by Dunnett's method. * p < 0.05, ** p < 0.01 vs. control group .
Table 5
The results are expressed as means ± SEM (n = 6) . Statistical differences between groups were assessed by Dunnett's method. * p < 0.05, ** p < 0.01 vs. control group .
Table 6:
The results are expressed as means ± SEM (n = 5 or 6) . Statistical differences between groups were assessed by Dunnett ' s method.
* p < 0.05, ** p < 0.01 vs. control group.
As shown in Tables 4-6, the combination treatment of an SGLT inhibitor and a DPP4 inhibitor produced marked and prolonged increase of plasma active GLP-I level in DPP4- positive rats.
These results suggest that the combination of an SGLT inhibitor and a DPP4 inhibitor provided substantial elevation of plasma active GLP-I level.
According to the present invention, a combination of an SGLT inhibitor and a DPP4 inhibitor can be used to prevent or treat some sort of disease which is associated with plasma active GLP-I level with a dose of a DPP4 inhibitor substantially lower than that currently contemplated for use in monotherapy for said condition, thereby reducing the likelihood of unwanted side-effects associated with inhibition of DPP4 activity.

Claims

Claims
1. A method for treating or preventing diabetes or a condition related to diabetes comprising administering to a patient in need thereof a therapeutically effective amount of an SGLT inhibitor and a DPP4 inhibitor.
2. A method according to claim 1, wherein the SGLT inhibitor and the DPP4 inhibitor are administered in amounts sufficient to lower a blood glucose level in the patient .
3. A method for preventing or treating a disease which is associated with plasma active GLP-I level comprising administering to a patient in need thereof a therapeutically effective amount of an SGLT inhibitor and a DPP4 inhibitor.
4. A method according to claim 3 , wherein the SGLT inhibitor and the DPP4 inhibitor are administered in amounts sufficient to increase plasma active GLP-I level in the patient.
5. A method for increasing plasma active GLP-I level comprising administering to a patient a therapeutically effective amount of an SGLT inhibitor and a DPP4 inhibitor.
6. A method according to claim 1, wherein diabetes is Type 2 diabetes .
7. A method according to claim 3, wherein the disease which is associated with plasma active GLP-I level is selected from diabetes, a condition related to diabetes, myocardial infarction, learning impairment, memory impairment, stroke and a neurodegenerative disorder.
8. A method according to claim 1 or 7, wherein the condition related to diabetes is selected from hyperglycemia, impaired glucose tolerance, impaired fasting glucose, insulin resistance, pancreatic beta-cell insuffi- ciency, enteroendocrine cell insufficiency, glucosuria, metabolic acidosis, cataracts, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic coronary artery disease, diabetic cerebrovascular disease, diabetic peripheral vascular disease, metabolic syndrome, hyperlipidemia, atherosclerosis, hypertension, and obesity.
9. A method according to claim 7 , wherein the neurodegenerative disorder is selected from excitotoxic brain damage caused by severe epileptic seizures, Alzheimer's disease, Parkinson's disease, Huntington's disease, prion-associated disease, motor-neuron disease, traumatic brain injury, spinal cord injury, and peripheral neuropathy.
10. A pharmaceutical composition comprising an SGLT inhibitor, a DPP4 inhibitor and a pharmaceutically acceptable carrier or diluent, wherein the SGLT inhibitor and the DPP4 inhibitor are in amounts sufficient to increase plasma active GLP-I level in a patient.
11. A method of preventing or treating diabetes or a condition related thereto comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition as set forth in claim 10.
12. A method of preventing or treating a disease which is associated with plasma active GLP-I level comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition as set forth in claim 10.
13. A method of increasing plasma active GLP-I level comprising administering to a patient a therapeutically effective amount of the pharmaceutical composition as set forth in claim 10.
14. The method according to claim 1, wherein the SGLT inhibitor is a compound of Formula (23) :
wherein Ring A and Ring B are one of the followings: (1) Ring A is optionally substituted unsaturated heteromono- cyclic, and Ring B is optionally substituted unsaturated heteromonocyclic, optionally substituted unsaturated fused heterobicyclic, or optionally substituted benzene, (2) Ring A is optionally substituted benzene, and Ring B is optionally substituted unsaturated heteromonocyclic, or optionally substituted unsaturated fused heterobicyclic wherein Y is linked to the heterocyclic ring of said fused heterobicyclic, or (3) Ring A is optionally substituted unsaturated fused heterobicyclic, wherein the sugar moiety X- (sugar) and the moiety -Y- (Ring B) are both on the same heterocyclic ring of said fused heterobicyclic, and Ring B is optionally substituted unsaturated heteromonocyclic, optionally substituted unsaturated fused heterobicyclic, or optionally substituted benzene; X is carbon or nitrogen,- and
Y is - (CH2) n- (wherein n is 1 or 2); or a pharmaceutically acceptable salt thereof.
15. The method according to claim 1, wherein the SGLT inhibitor is a compound of Formula (24) :
(24) wherein RA is a halogen atom, or a lower alkyl group; Ring C is a phenyl group substituted by 1-3 substituents selected from the group consisting of a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group, a methylenedioxy group, an ethyleneoxy group, a mono- or di- lower alkylamino group, a carbamoyl group, and a mono- or di-lower alkylcarbamoyl group; or a heterocyclyl group substituted by 1-3 substituents selected from the group consisting of a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group, a mono- or di-lower alkylamino group, a carbamoyl group, and a mono- or di-lower alkylcarbamoyl group; or a pharmaceutically acceptable salt thereof.
16. The method according to claim 1, wherein the SGLT inhibitor is a compound of Formula (25) :
(25) wherein R1 is halogen, or alkyl, R2 is hydrogen, or halogen, and Ar is one of the following groups :
in which R3 and R4 are independently hydrogen, halogen, alkyl, cycloalkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, hydroxy, phenyl, halophenyl, cyanophenyl, pyridyl, halopyridyl, thienyl, or halothienyl, or R3 and R4 together with carbon atoms to which they are attached form a fused benzene, furan or dihydrofuran ring,- or a pharmaceutically acceptable salt thereof.
17. The method according to claim 1, wherein the SGLT inhibitor is a compound of Formula (26) :
OH (26) wherein R1 is fluorine, or chlorine, and R2 is hydrogen, or fluorine, or a pharmaceutically acceptable salt thereof.
18. The method according to claim 1, wherein the DPP4 inhibitor is a compound of Formula (29) :
wherein A represents -CH2- or -S-, R1 represents hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group or a lower alkoxy lower alkyl group, and R2 represents (1) a cyclic group which may be substituted, where the cyclic group portion is (i) a monocyclic, bicyclic or tricyclic hydrocarbon group, or (ii) a monocyclic, bicyclic or tricyclic heterocyclic group, or (2) an amino group which may be substituted, or a pharmaceutically acceptable salt thereof .
19. The method according to claim 1, wherein the DPP4 inhibitor is a compound of Formula (30) :
wherein A is -CH2-, R1 is H, a lower alkyl group, a hydroxy lower alkyl group or a lower alkoxy lower alkyl group, and R2 is a piperazinyl group which may be substituted, or a pharmaceutically acceptable salt thereof .
20. The method according to claim 1, wherein the SGLT inhibitor is Sergliflozin, Remogliflozin or Dapagliflozin, and the DPP4 inhibitor is Sitagliptin, Vildagliptin, Saxagliptin or Alogliptin.
21. The method according to claim 1, wherein the SGLT inhibitor is a compound of Formula (23) :
wherein Ring A and Ring B are one of the followings : (1) Ring A is optionally substituted unsaturated hetero- monocyclic, and Ring B is optionally substituted unsaturated heteromonocyclic, optionally substituted unsaturated fused heterobicyclic, or optionally substituted benzene, (2) Ring A is optionally substituted benzene, and Ring B is optionally substituted unsaturated heteromono- cyclic, or optionally substituted unsaturated fused hetero- bicyclic wherein Y is linked to the heterocyclic ring of said fused heterobicyclic, or (3) Ring A is optionally substituted unsaturated fused heterobicyclic, wherein the sugar moiety X- (sugar) and the moiety -Y- (Ring B) are both on the same heterocyclic ring of said fused heterobicyclic, and Ring B is optionally substituted unsaturated hetero- monocyclic, optionally substituted unsaturated fused heterobicyclic, or optionally substituted benzene; X is carbon or nitrogen,- and Y is - (CH2) n- (wherein n is 1 or 2) ; or a pharmaceutically acceptable salt thereof; and the DPP4 inhibitor is a compound of formula (28) :
wherein A represents -CH2- or -S-, R1 represents hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group or a lower alkoxy lower alkyl group, and R2 represents (1) a cyclic group which may be substituted, where the cyclic group portion is (i) a monocyclic, bicyclic or tricyclic hydrocarbon group, or (ii) a monocyclic, bicyclic or tricyclic heterocyclic group, or (2) an amino group which may be substituted, or pharmaceutically acceptable slat thereof ,- or a compound of Formula (31) :
wherein :
X is -NR1R2 wherein R1 and R2 may be the same or different and each is independently cycloalkylalkyl, arylalkyl, heteroaryl or heteroarylalkyl, or may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents, and the heterocycle optionally being a spiro ring, -NR3COR4 wherein R3 and R4 are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl or heteroarylalkyl, -NR5CONR6R7 or -NR5CH2CH2NR5R7 wherein R5, R6 and R7 are the same or different and each is independently hydrogen atom, alkyl, acyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or Rs and R7 may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents,
-NR8SO2R9 wherein R8 and R9 are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or
-OR10 or -OCOR11 wherein R10 and R11 are each a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, Y is CH2, CH-OH, S, S=O or SO2, Z is a hydrogen atom or cyano, and of the above-mentioned groups, alkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl and heterocycle each optionally have substituents, or a pharmaceutically acceptable salt thereof; or
Sitagliptin or a pharmaceutically acceptable salt thereof .
22. The method according to claim 1, wherein the SGLT inhibitor is a compound of Formula (24) :
(24) wherein RA is a halogen atom, or a lower alkyl group,- Ring C is a phenyl group substituted by 1-3 substituents selected from the group consisting of a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group, a methyl- enedioxy group, an ethyleneoxy group, a mono- or di-lower alkylamino group, a carbamoyl group, and a mono- or di- lower alkylcarbamoyl group; or a heterocyclyl group substituted by 1-3 substituents selected from the group consisting of a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group, a mono- or di-lower alkylamino group, a carbamoyl group, and a mono- or di-lower alkyl- carbamoyl group,- or a pharmaceutically acceptable salt thereof, or a prodrug thereof ,- and the DPP4 inhibitor is a compound of formula (29) :
wherein A represents -CH2- or -S-, R1 represents hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group or a lower alkoxy lower alkyl group, and R2 represents (1) a cyclic group which may be substituted, where the cyclic group portion is (i) a monocyclic, bicyclic or tricyclic hydrocarbon group, or (ii) a monocyclic, bicyclic or tricyclic heterocyclic group, or (2) an amino group which may be substituted, or pharmaceutically acceptable slat thereof; or a compound of Formula (31) :
wherein :
X is -NR1R2 wherein R1 and R2 may be the same or different and each is independently cycloalkylalkyl, arylalkyl, heteroaryl or heteroarylalkyl , or may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents, and the heterocycle optionally being a spiro ring, -NR3COR4 wherein R3 and R4 are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl or heteroarylalkyl,
-NR5CONR5R7 or -NR5CH2CH2NR6R7 wherein R5, R6 and R7 are the same or different and each is independently hydrogen atom, alkyl, acyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or Rs and R7 may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents,
-NR8SO2R9 wherein R8 and R9 are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or hetero- arylalkyl , or
-OR10 or -OCOR11 wherein R10 and R11 are each a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl,
Y is CH2, CH-OH, S, S=O or SO2,
Z is a hydrogen atom or cyano, and of the above-mentioned groups, alkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl and heterocycle each optionally have substituents, or a pharmaceutically acceptable salt thereof; or
Sitagliptin or a pharmaceutically acceptable salt thereof .
23. The method according to claim 1, wherein the SGLT inhibitor is a compound of Formula (26) :
(26) wherein R1 is fluorine, or chlorine, and R2 is hydrogen, or fluorine, or a pharmaceutically acceptable salt thereof; and the DPP4 inhibitor is a compound of formula (29) :
wherein A represents -CH2- or -S-, R1 represents hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group or a lower alkoxy lower alkyl group, and R2 represents (1) a cyclic group which may be substituted, where the cyclic group portion is (i) a monocyclic, bicyclic or tricyclic hydrocarbon group, or (ii) a monocyclic, bicyclic or tricyclic heterocyclic group, or (2) an amino group which may be substituted, or pharmaceutically acceptable slat thereof ; or a compound of Formula (31) :
wherein:
X is -NR1R2 wherein R1 and R2 may be the same or different and each is independently cycloalkylalkyl, arylalkyl, heteroaryl or heteroarylalkyl, or may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents, and the heterocycle optionally being a spiro ring, -NR3COR4 wherein R3 and R4 are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl or heteroarylalkyl,
-NR5CONR5R7 or -NR5CH2CH2NR5R7 wherein R5, Rs and R7 are the same or different and each is independently hydrogen atom, alkyl, acyl , cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or Re and R7 may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents,
-NR8SO2R9 wherein R8 and R9 are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or hetero- arylalkyl , or
-OR10 or -OCOR11 wherein R10 and R11 are each a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl,
Y is CH2, CH-OH, S, S=O or SO2,
Z is a hydrogen atom or cyano, and of the above-mentioned groups, alkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl and heterocycle each optionally have substituents, or a pharmaceutically acceptable salt thereof; or
Sitagliptin or a pharmaceutically acceptable salt thereof .
24. The method according to claim 1, wherein the SGLT inhibitor is selected from:
1- (β-D-Glucopyranosyl) -4-chloro-3- [5- (6-fluoro-2-pyridyl) - 2 -thienylmethyl] benzene or a pharmaceutically acceptable salt thereof;
3- (5- (4-Fluorophenyl) -2 -thienylmethyl) -1- (β-D-glucopyrano- syl) -4-methylbenzene or a pharmaceutically acceptable salt thereof ;
1- (β-D-Glucopyranosyl) -4-chloro-3- [5- (6-fluoro-3-pyridyl) - 2-thienylmethyl] benzene or a pharmaceutically acceptable salt thereof ,-
3- (4-Cyclopropylphenylmethyl) -4-fluoro-l- (β-D-glucopyrano- syl) indole or a pharmaceutically acceptable salt thereof; and 3- (4-Cyclopropylphenylmethyl) -4 , 6-difluoro-1- (β-D-gluco- pyranosyl) indole or a pharmaceutically acceptable salt thereof ; and the DPP4 inhibitor is selected from: 3- [ (2S, 4S) -4- [4- (3 -methyl-1-phenyl-lH-pyrazol-5 -yDpipera- zin-l-yl] pyrrolidin-2-ylcarbonyl] thiazolidine or a pharmaceutically acceptable salt thereof; Sitagliptin or a pharmaceutically acceptable salt thereof; and
(2S) -2-cyano-l- [trans-4- (dimethylaminocarbonyl) cyclohexyl- amino] acetylpyrrolidine or a pharmaceutically acceptable salt thereof.
25. The pharmaceutical composition according to claim 10, wherein the SGLT inhibitor is a compound of Formula (23) :
wherein Ring A and Ring B are one of the followings: (1) Ring A is optionally substituted unsaturated heteromono- cyclic, and Ring B is optionally substituted unsaturated heteromonocyclic, optionally substituted unsaturated fused heterobicyclic, or optionally substituted benzene, (2) Ring A is optionally substituted benzene, and Ring B is optionally substituted unsaturated heteromonocyclic, or optionally substituted unsaturated fused heterobicyclic wherein Y is linked to the heterocyclic ring of said fused heterobicyclic, or (3) Ring A is optionally substituted unsaturated fused heterobicyclic, wherein the sugar moiety X- (sugar) and the moiety -Y- (Ring B) are both on the same heterocyclic ring of said fused heterobicyclic, and Ring B is optionally substituted unsaturated heteromonocyclic, optionally substituted unsaturated fused heterobicyclic, or optionally substituted benzene ; X is carbon or nitrogen; and
Y is -(CH2)n- (wherein n is 1 or 2); or a pharmaceutically acceptable salt thereof; and the DPP4 inhibitor is a compound of formula (29) : wherein A represents -CH2- or -S-, R1 represents hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group or a lower alkoxy lower alkyl group, and R2 represents (1) a cyclic group which may be substituted, where the cyclic group portion is (i) a monocyclic, bicyclic or tricyclic hydrocarbon group, or (ii) a monocyclic, bicyclic or tricyclic heterocyclic group, or (2) an amino group which may be substituted, or pharmaceutically acceptable slat thereof; or the DPP4 inhibitor is a compound of Formula (31) :
wherein:
X is -NR1R2 wherein R1 and R2 may be the same or different and each is independently cycloalkylalkyl, arylalkyl, heteroaryl or heteroarylalkyl , or may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents, and the heterocycle optionally being a spiro ring,
-NR3COR4 wherein R3 and R4 are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl or heteroarylalkyl,
-NR5CONR6R7 or -NR5CH2CH2NR5R7 wherein R5, R6 and R7 are the same or different and each is independently hydrogen atom, alkyl, acyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl , or Rs and R7 may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents,
-NR8SO2R9 wherein R8 and R9 are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl , or -OR10 or -OCOR11 wherein R10 and R11 are each a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, Y is CH2, CH-OH, S, S=O or SO2, Z is a hydrogen atom or cyano, and of the above-mentioned groups, alkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl and heterocycle each optionally have substituents , or a pharmaceutically acceptable salt thereof; or the DPP4 inhibitor is Sitagliptin or a pharmaceutically acceptable salt thereof.
26. The pharmaceutical composition according to claim 10, wherein the SGLT inhibitor is a compound of Formula (24) :
(24) wherein RA is a halogen atom, or a lower alkyl group; Ring C is a phenyl group substituted by 1-3 substituents selected from the group consisting of a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group, a methyl- enedioxy group, an ethyleneoxy group, a mono- or di-lower alkylamino group, a carbamoyl group, and a mono- or di- lower alkylcarbamoyl group,- or a heterocyclyl group substituted by 1-3 substituents selected from the group consisting of a halogen atom, a cyano group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group, a mono- or di-lower alkylamino group, a carbamoyl group, and a mono- or di-lower alkyl- carbamoyl group,- or a pharmaceutically acceptable salt thereof, or a prodrug thereof, and the DPP4 inhibitor is a compound of formula (29) :
R2-COi ( V--NH-CH2-CO-N A
CN (29) wherein A represents -CH2- or -S-, R1 represents hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group or a lower alkoxy lower alkyl group, and R2 represents (1) a cyclic group which may be substituted, where the cyclic group portion is (i) a monocyclic, bicyclic or tricyclic hydrocarbon group, or (ii) a monocyclic, bicyclic or tricyclic heterocyclic group, or (2) an amino group which may be substituted, or pharmaceutically acceptable slat thereof; or the DPP4 inhibitor is a compound of Formula (31) :
wherein :
X is -NR1R2 wherein R1 and R2 may be the same or different and each is independently cycloalkylalkyl, arylalkyl, heteroaryl or heteroarylalkyl , or may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents, and the heterocycle optionally being a spiro ring,
-NR3COR4 wherein R3 and R4 are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl or heteroarylalkyl,
-NR5CONR5R7 or -NR5CH2CH2NR6R7 wherein R5, R6 and R7 are the same or different and each is independently hydrogen atom, alkyl, acyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or R6 and R7 may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents, -NR8SO2R9 wherein R8 and R9 are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl , or
-OR10 or -OCOR11 wherein R10 and R11 are each a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, Y is CH2, CH-OH, S, S=O or SO2, Z is a hydrogen atom or cyano, and of the above-mentioned groups, alkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl and heterocycle each optionally have substituents, or a pharmaceutically acceptable salt thereof; or the DPP4 inhibitor is Sitagliptin or a pharmaceutically acceptable salt thereof.
27. The pharmaceutical composition according to claim 10, wherein the SGLT inhibitor is a compound of Formula (26) :
(26) wherein R1 is fluorine, or chlorine, and R2 is hydrogen, or fluorine, or a pharmaceutically acceptable salt thereof; and the DPP4 inhibitor is a compound of formula (29) :
wherein A represents -CH2- or -S-, R1 represents hydrogen atom, a lower alkyl group, a hydroxy lower alkyl group or a lower alkoxy lower alkyl group, and R2 represents (1) a cyclic group which may be substituted, where the cyclic group portion is (i) a monocyclic, bicyclic or tricyclic hydrocarbon group, or (ii) a monocyclic, bicyclic or tricyclic heterocyclic group, or (2) an amino group which may be substituted, or a pharmaceutically acceptable slat thereof; or the DPP4 inhibitor is a compound of Formula (31) :
wherein:
X is -NR1R2 wherein R1 and R2 may be the same or different and each is independently cycloalkylalkyl, arylalkyl, heteroaryl or heteroarylalkyl , or may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents, and the heterocycle optionally being a spiro ring,
-NR3COR4 wherein R3 and R4 are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl or heteroarylalkyl,
-NR5CONR5R7 or -NR5CH2CH2NR6R7 wherein R5, R6 and R7 are the same or different and each is independently hydrogen atom, alkyl, acyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or R6 and R7 may be bonded to each other to form a heterocycle optionally containing 1 or 2 nitrogen atoms or oxygen atoms, the heterocycle optionally being condensed with an aromatic ring optionally having substituents, -NR8SO2R9 wherein R8 and R9 are the same or different and each is independently a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, or
-OR10 or -OCOR11 wherein R10 and R11 are each a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, Y is CH2, CH-OH, S, S=O or SO2, Z is a hydrogen atom or cyano, and of the above-mentioned groups, alkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl and heterocycle each optionally have substituents , or a pharmaceutically acceptable salt thereof; or the DPP4 inhibitor is Sitagliptin or a pharmaceutically acceptable salt thereof.
28. The pharmaceutical composition according to claim 10, wherein the SGLT inhibitor is selected from: 1- (β-D-Glucopyranosyl) -4-chloro-3- [5- (6-fluoro-2-pyridyl) - 2-thienylmethyl] benzene or a pharmaceutically acceptable salt thereof; 3- (5- (4-Fluorophenyl) -2 -thienylmethyl) -1- (β-D-glucopyrano- syl) -4-methylbenzene or a pharmaceutically acceptable salt thereof;
1- (β-D-Glucopyranosyl) -4-chloro-3- [5- (6-fluoro-3-pyridyl) - 2-thienylmethyl] benzene or a pharmaceutically acceptable salt thereof;
3- (4-Cyclopropylphenylmethyl) -4-fluoro-1- (β-D-glucopyrano- syl) indole or a pharmaceutically acceptable salt thereof; and
3- (4-Cyclopropylphenylmethyl) -4 , 6-difluoro-1- (β-D-gluco- pyranosyl) indole or a pharmaceutically acceptable salt thereof ; and the DPP4 inhibitor is selected from:
3- t (2S,4S) -4- [4- (3 -methyl-1-phenyl-IH-pyrazol-5-yDpipera- zin-l-yl] pyrrolidin-2 -ylcarbonyl] thiazolidine or a pharma- ceutically acceptable salt thereof;
Sitagliptin or a pharmaceutically acceptable salt thereof; and
(2S) -2-cyano-l- [trans-4- (dimethylaminocarbonyl) cyclohexyl- amino] acetylpyrrolidine or a pharmaceutically acceptable salt thereof.
29. Use of an SGLT inhibitor in combination with a DPP4 inhibitor as active ingredients for manufacture of a pharmaceutical preparation for treating or preventing a disease associated with plasma active GLP-I level.
30. A product containing an SGLT inhibitor and a DPP4 inhibitor as a combined preparation for simultaneous, separate or sequential administration for preventing or treating a disease associated with plasma active GLP-I level .
EP09701670.3A 2008-01-17 2009-01-16 Combination therapy comprising sglt inhibitors and dpp4 inhibitors Active EP2252289B1 (en)

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